Collagen () is the main structural
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
in the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...
of the
connective tissue
Connective tissue is one of the four primary types of animal tissue, a group of cells that are similar in structure, along with epithelial tissue, muscle tissue, and nervous tissue. It develops mostly from the mesenchyme, derived from the mesod ...
s of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content.
Amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s are bound together to form a
triple helix of elongated
fibril
Fibrils () are structural biological materials found in nearly all living organisms. Not to be confused with fibers or protein filament, filaments, fibrils tend to have diameters ranging from 10 to 100 nanometers (whereas fibers are micro to ...
known as a
collagen helix
In molecular biology, the collagen triple helix or type-2 helix is the main secondary structure of various types of fibrous collagen, including type I collagen. In 1954, Ramachandran & Kartha (13, 14) advanced a structure for the collagen tripl ...
. It is mostly found in
cartilage
Cartilage is a resilient and smooth type of connective tissue. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...
,
bone
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...
s,
tendon
A tendon or sinew is a tough band of fibrous connective tissue, dense fibrous connective tissue that connects skeletal muscle, muscle to bone. It sends the mechanical forces of muscle contraction to the skeletal system, while withstanding tensi ...
s,
ligament
A ligament is a type of fibrous connective tissue in the body that connects bones to other bones. It also connects flight feathers to bones, in dinosaurs and birds. All 30,000 species of amniotes (land animals with internal bones) have liga ...
s, and
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different ...
.
Vitamin C
Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits, berries and vegetables. It is also a generic prescription medication and in some countries is sold as a non-prescription di ...
is vital for collagen synthesis.
Depending on the degree of
mineralization, collagen tissues may be rigid (bone) or compliant (tendon) or have a gradient from rigid to compliant (cartilage). Collagen is also abundant in
cornea
The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...
s,
blood vessel
Blood vessels are the tubular structures of a circulatory system that transport blood throughout many Animal, animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the Tissue (biology), tissues of a Body (bi ...
s, the
gut,
intervertebral disc
An intervertebral disc (British English), also spelled intervertebral disk (American English), lies between adjacent vertebrae in the vertebral column. Each disc forms a fibrocartilaginous joint (a symphysis), to allow slight movement of the ver ...
s, and the
dentin
Dentin ( ) (American English) or dentine ( or ) (British English) () is a calcified tissue (biology), tissue of the body and, along with tooth enamel, enamel, cementum, and pulp (tooth), pulp, is one of the four major components of teeth. It i ...
in teeth. In
muscle tissue
Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to contract. ...
, it serves as a major component of the
endomysium. Collagen constitutes 1% to 2% of muscle tissue and 6% by weight of
skeletal muscle
Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...
. The
fibroblast
A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...
is the most common cell creating collagen in animals.
Gelatin
Gelatin or gelatine () is a translucent, colorless, flavorless food ingredient, commonly derived from collagen taken from animal body parts. It is brittle when dry and rubbery when moist. It may also be referred to as hydrolyzed collagen, coll ...
, which is used in food and industry, is collagen that was irreversibly
hydrolyzed
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysi ...
using heat, basic solutions, or weak acids.
Etymology
The name ''collagen'' comes from the Greek
κόλλα (''kólla''), meaning "
glue
Adhesive, also known as glue, cement, mucilage, or paste, is any non-metallic substance applied to one or both surfaces of two separate items that binds them together and resists their separation.
The use of adhesives offers certain advantage ...
", and suffix -γέν, ''-gen'', denoting "producing".
Types
As of 2011, 28 types of human collagen have been identified, described, and classified according to their structure.
This diversity shows collagen's diverse functionality.
All of the types contain at least one
triple helix.
Over 90% of the collagen in
humans
Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...
is
type I & III collagen
Type may refer to:
Science and technology Computing
* Typing, producing text via a keyboard, typewriter, etc.
* Data type, collection of values used for computations.
* File type
* TYPE (DOS command), a command to display contents of a file.
* ...
.
* Fibrillar (type I, II, III, V, XI)
* Non-fibrillar
**
FACIT (fibril-associated collagens with interrupted triple helices) (types IX, XII, XIV, XIX, XXI)
** Short-chain (types VIII, X)
**
Basement membrane
The basement membrane, also known as base membrane, is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between epithelial tis ...
(type IV)
**
Multiplexin (multiple triple helix domains with interruptions) (types XV, XVIII)
** MACIT (membrane-associated collagens with interrupted triple helices) (types XIII, XVII)
** Microfibril-forming (type VI)
**
Anchoring fibrils (type VII)
The five most common types are:
*
Type I: skin,
tendon
A tendon or sinew is a tough band of fibrous connective tissue, dense fibrous connective tissue that connects skeletal muscle, muscle to bone. It sends the mechanical forces of muscle contraction to the skeletal system, while withstanding tensi ...
, vasculature, organs,
bone
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...
(main component of the organic part of bone)
*
Type II:
cartilage
Cartilage is a resilient and smooth type of connective tissue. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...
(main collagenous component of cartilage)
*
Type III: reticulate (main component of
reticular fibers), commonly found alongside type I
*
Type IV: forms basal lamina, the epithelium-secreted layer of the
basement membrane
The basement membrane, also known as base membrane, is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between epithelial tis ...
*
Type V: cell surfaces, hair, and
placenta
The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...
In humans
Cardiac
The collagenous
cardiac skeleton, which includes the four
heart valve
A heart valve is a biological one-way valve that allows blood to flow in one direction through the chambers of the heart. A mammalian heart usually has four valves. Together, the valves determine the direction of blood flow through the heart. Hea ...
rings, is histologically, elastically and uniquely bound to cardiac muscle. The cardiac skeleton also includes the separating
septa of the heart chambers – the
interventricular septum
The interventricular septum (IVS, or ventricular septum, or during development septum inferius) is the stout wall separating the ventricle (heart), ventricles, the lower chambers of the heart, from one another.
The interventricular septum is di ...
and the
atrioventricular septum. Collagen contribution to the measure of
cardiac performance summarily represents a continuous torsional force opposed to the
fluid mechanics
Fluid mechanics is the branch of physics concerned with the mechanics of fluids (liquids, gases, and plasma (physics), plasmas) and the forces on them.
Originally applied to water (hydromechanics), it found applications in a wide range of discipl ...
of blood pressure emitted from the heart. The collagenous structure that divides the upper chambers of the heart from the lower chambers is an impermeable membrane that excludes both blood and electrical impulses through typical physiological means. With support from collagen,
atrial fibrillation
Atrial fibrillation (AF, AFib or A-fib) is an Heart arrhythmia, abnormal heart rhythm (arrhythmia) characterized by fibrillation, rapid and irregular beating of the Atrium (heart), atrial chambers of the heart. It often begins as short periods ...
never deteriorates to
ventricular fibrillation
Ventricular fibrillation (V-fib or VF) is an abnormal heart rhythm in which the Ventricle (heart), ventricles of the heart Fibrillation, quiver. It is due to disorganized electrical conduction system of the heart, electrical activity. Ventricula ...
. Collagen is layered in variable densities with smooth muscle mass. The mass, distribution, age, and density of collagen all contribute to the
compliance required to move blood back and forth. Individual cardiac valvular leaflets are folded into shape by specialized collagen under variable
pressure
Pressure (symbol: ''p'' or ''P'') is the force applied perpendicular to the surface of an object per unit area over which that force is distributed. Gauge pressure (also spelled ''gage'' pressure)The preferred spelling varies by country and eve ...
. Gradual
calcium
Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
deposition within collagen occurs as a natural function of aging. Calcified points within collagen matrices show contrast in a moving display of blood and muscle, enabling methods of
cardiac imaging
Cardiac imaging refers to minimally invasive imaging of the heart using ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), or nuclear medicine (NM) imaging with Positron emission tomography, PET or SPECT. These cardiac techniq ...
technology to arrive at ratios essentially stating blood in (
cardiac input) and blood out (
cardiac output
In cardiac physiology, cardiac output (CO), also known as heart output and often denoted by the symbols Q, \dot Q, or \dot Q_ , edited by Catherine E. Williamson, Phillip Bennett is the volumetric flow rate of the heart's pumping output: tha ...
). Pathology of the collagen underpinning of the heart is understood within the category of
connective tissue disease.
Bone grafts
As the skeleton forms the structure of the body, it is vital that it maintains its strength, even after breaks and injuries. Collagen is used in bone grafting because its triple-helix structure makes it a very strong molecule. It is ideal for use in bones, as it does not compromise the structural integrity of the skeleton. The triple helical structure prevents collagen from being broken down by enzymes, it enables adhesiveness of cells and it is important for the proper assembly of the extracellular matrix.
Tissue regeneration
Collagen scaffolds are used in tissue regeneration, whether in sponges, thin sheets, gels, or fibers. Collagen has favorable properties for tissue regeneration, such as pore structure, permeability,
hydrophilicity, and stability in vivo. Collagen scaffolds also support deposition of cells, such as
osteoblasts and
fibroblast
A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...
s, and once inserted, facilitate growth to proceed normally.
Reconstructive surgery
Collagens are widely used in the construction of
artificial skin substitutes used for managing severe
burns and wounds.
These collagens may be derived from cow, horse, pig, or even human sources; and are sometimes used in combination with
silicone
In Organosilicon chemistry, organosilicon and polymer chemistry, a silicone or polysiloxane is a polymer composed of repeating units of siloxane (, where R = Organyl group, organic group). They are typically colorless oils or elastomer, rubber ...
s,
glycosaminoglycans, fibroblasts,
growth factor
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for ...
s and other substances.
Wound healing
Collagen is one of the body's key natural resources and a component of skin tissue that can benefit all stages of
wound healing
Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue.
In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...
.
When collagen is made available to the wound bed, closure can occur. This avoids wound deterioration and procedures such as amputation.
Collagen is used as a natural wound dressing because it has properties that artificial wound dressings do not have. It resists bacteria, which is vitally important in wound dressing. As a burn dressing, collagen helps it heal fast by helping
granulation tissue
Granulation tissue is new connective tissue and microscopic blood vessels that form on the surfaces of a wound during the healing process. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size ...
to grow over the burn.
Throughout the four phases of wound healing, collagen performs the following functions:
* Guiding:
collagen fibers
Type I collagen is the most abundant collagen of the human body, consisting of around 90% of the body's total collagen in vertebrates. Due to this, it is also the most abundant protein type found in all vertebrates. Type I forms large, eosinoph ...
guide fibroblasts because they migrate along a connective tissue matrix.
*
Chemotaxis
Chemotaxis (from ''chemical substance, chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell organism, single-cell or multicellular organisms direct thei ...
: collagen fibers have a large surface area which attracts fibrogenic cells which help healing.
*
Nucleation
In thermodynamics, nucleation is the first step in the formation of either a new Phase (matter), thermodynamic phase or Crystal structure, structure via self-assembly or self-organization within a substance or mixture. Nucleation is typically def ...
: in the presence of certain neutral salt molecules, collagen can act as a nucleating agent causing formation of fibrillar structures.
*
Hemostasis
In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. Hemostasis involves three ...
: Blood
platelet
Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
s interact with the collagen to make a hemostatic plug.
Use in basic research
Collagen is used in
laboratory studies for
cell culture
Cell culture or tissue culture is the process by which cell (biology), cells are grown under controlled conditions, generally outside of their natural environment. After cells of interest have been Cell isolation, isolated from living tissue, ...
, studying cell behavior and cellular interactions with the
extracellular environment. Collagen is also widely used as a
bioink for
3D bioprinting and
biofabrication
Biofabrication is a branch of biotechnology specialising in the research and development of Biological engineering, biologically engineered processes for the Automation, automated production of Biological activity, biologically functional product ...
of 3D tissue models.
Biology
The collagen protein is composed of a triple helix, which generally consists of two identical chains (α1) and an additional chain that differs slightly in its chemical composition (α2). The amino acid composition of collagen is atypical for proteins, particularly with respect to its high
hydroxyproline
(2''S'',4''R'')-4-Hydroxyproline, or L-hydroxyproline ( C5 H9 O3 N), is an amino acid, abbreviated as Hyp or O, ''e.g.'', in Protein Data Bank.
Structure and discovery
In 1902, Hermann Emil Fischer isolated hydroxyproline from hydrolyzed gela ...
content. The most common motifs in collagen's amino acid sequence are
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...
-
proline
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...
-X and glycine-X-hydroxyproline, where X is any amino acid other than glycine, proline or hydroxyproline.
The table below lists average amino acid composition for fish and mammal skin.
Synthesis
First, a three-dimensional stranded structure is assembled, mostly composed of the amino acids glycine and proline. This is the collagen precursor procollagen. Then, procollagen is modified by the addition of
hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
groups to the amino acids proline and
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...
. This step is important for later
glycosylation
Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
and the formation of collagen's triple helix structure. Because the
hydroxylase
In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate Alcohol (chemistry), alcohols and phenols, which are very common functional groups. Hydroxylation confers some degre ...
enzymes performing these reactions require
vitamin C
Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits, berries and vegetables. It is also a generic prescription medication and in some countries is sold as a non-prescription di ...
as a
cofactor, a long-term deficiency in this vitamin results in impaired collagen synthesis and
scurvy
Scurvy is a deficiency disease (state of malnutrition) resulting from a lack of vitamin C (ascorbic acid). Early symptoms of deficiency include weakness, fatigue, and sore arms and legs. Without treatment, anemia, decreased red blood cells, gum d ...
. These hydroxylation reactions are catalyzed by the enzymes
prolyl 4-hydroxylase and
lysyl hydroxylase. The reaction consumes one ascorbate molecule per hydroxylation. Collagen synthesis occurs inside and outside cells.
The most common form of collagen is fibrillary collagen. Another common form is meshwork collagen, which is often involved in the formation of filtration systems. All types of collagen are triple helices, but differ in the make-up of their alpha peptides created in step 2. Below we discuss the formation of fibrillary collagen.
# Transcription of mRNA: Synthesis begins with turning on genes associated with the formation of a particular alpha peptide (typically alpha 1, 2 or 3). About 44 genes are associated with collagen formation, each coding for a specific mRNA sequence, and are typically named with the "''COL''" prefix.
# Pre-pro-peptide formation: The created mRNA exits the cell nucleus into the cytoplasm. There, it links with the ribosomal subunits and is translated into a peptide. The peptide goes into the endoplasmic reticulum for post-translational processing. It is directed there by a
signal recognition particle
The signal recognition particle (SRP) is an abundant, cytosolic, universally conserved ribonucleoprotein (protein-RNA complex) that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma membrane ...
on the
endoplasmic reticulum
The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
, which recognizes the peptide's signal sequence (the early part of the sequence). The processed product is a
pre-pro-peptide called preprocollagen.
# Pro-collagen formation: Three modifications of the pre-pro-peptide form the alpha peptide:
## The signal peptide on the N-terminal is removed. This molecule is called ''propeptide.''
## Lysines and prolines are hydroxylated by the enzymes 'prolyl hydroxylase' and 'lysyl hydroxylase', producing hydroxyproline and hydroxylysine. This helps in cross-linking the alpha peptides. This enzymatic step requires vitamin C as a cofactor. In scurvy, the lack of hydroxylation of prolines and lysines causes a looser triple helix (which is formed by three alpha peptides).
## Glycosylation occurs by adding either glucose or galactose monomers onto the hydroxyl groups that were placed onto lysines, but not on prolines.
## Three of the hydroxylated and glycosylated propeptides twist into a triple helix (except for its ends), forming procollagen. It is packaged into a transfer vesicle destined for the Golgi apparatus.
# Modification and secretion: In the
Golgi apparatus
The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...
, the procollagen goes through one last post-translational modification, adding oligosaccharides (not monosaccharides as in step 3). Then it is packaged into a secretory vesicle to be secreted from the cell.
# Tropocollagen formation: Outside the cell, membrane-bound enzymes called collagen peptidases remove the unwound ends of the molecule, producing tropocollagen. Defects in this step produce various collagenopathies called
Ehlers–Danlos syndrome. This step is absent when synthesizing type III, a type of fibrillar collagen.
# Collagen fibril formation:
Lysyl oxidase, a
copper-dependent enzyme, acts on lysines and hydroxylysines, producing aldehyde groups, which eventually form covalent bonds between tropocollagen molecules. This polymer of tropocollagen is called a collagen fibril.
Amino acids
Collagen has an unusual amino acid composition and sequence:
* Glycine is found at almost every third
residue.
* Proline makes up about 17% of collagen.
* Collagen contains two unusual derivative amino acids not directly inserted during
translation
Translation is the communication of the semantics, meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The English la ...
. These amino acids are found at specific locations relative to glycine and are modified post-translationally by different enzymes, both of which require vitamin C as a cofactor.
**
Hydroxyproline
(2''S'',4''R'')-4-Hydroxyproline, or L-hydroxyproline ( C5 H9 O3 N), is an amino acid, abbreviated as Hyp or O, ''e.g.'', in Protein Data Bank.
Structure and discovery
In 1902, Hermann Emil Fischer isolated hydroxyproline from hydrolyzed gela ...
derived from proline
**
Hydroxylysine derived from lysine – depending on the type of collagen, varying numbers of hydroxylysines are
glycosylated (mostly having
disaccharide
A disaccharide (also called a double sugar or ''biose'') is the sugar formed when two monosaccharides are joined by glycosidic linkage. Like monosaccharides, disaccharides are simple sugars soluble in water. Three common examples are sucrose, ...
s attached).
Cortisol
Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone.
Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...
stimulates
degradation of (skin) collagen into amino acids.
Collagen I formation
Most collagen forms in a similar manner, but the following process is typical for type I:
# Inside the cell
## Two types of alpha chains – alpha-1 and alpha 2, are formed during
translation
Translation is the communication of the semantics, meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The English la ...
on ribosomes along the
rough endoplasmic reticulum
The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for "little n ...
(RER). These peptide chains known as preprocollagen, have registration peptides on each end and a
signal peptide
A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16–30 amino acids long) present at the ...
.
## Polypeptide chains are released into the lumen of the RER.
## Signal peptides are cleaved inside the RER and these are known as pro-alpha chains.
##
Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on and consumes
ascorbic acid
Ascorbic acid is an organic compound with formula , originally called hexuronic acid. It is a white solid, but impure samples can appear yellowish. It dissolves freely in water to give mildly acidic solutions. It is a mild reducing agent.
Asco ...
(vitamin C) as a
cofactor.
##
Glycosylation
Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
of specific hydroxylysine residues occurs.
## Triple alpha helical structure is formed inside the endoplasmic reticulum from two alpha-1 chains and one alpha-2 chain.
##
Procollagen
Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
is shipped to the
Golgi apparatus
The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...
, where it is packaged and secreted into the extracellular space by
exocytosis
Exocytosis is a term for the active transport process that transports large molecules from cell to the extracellular area. Hormones, proteins and neurotransmitters are examples of large molecules that can be transported out of the cell. Exocytosis ...
.
# Outside the cell
## Registration peptides are cleaved, and tropocollagen is formed by
procollagen peptidase.
## Multiple tropocollagen molecules form collagen fibrils, via covalent cross-linking (
aldol reaction
The aldol reaction (aldol addition) is a Chemical reaction, reaction in organic chemistry that combines two Carbonyl group, carbonyl compounds (e.g. aldehydes or ketones) to form a new β-hydroxy carbonyl compound. Its simplest form might invol ...
) by
lysyl oxidase which links hydroxylysine and lysine residues. Multiple collagen fibrils form into collagen fibers.
## Collagen may be attached to cell membranes via several types of protein, including
fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as col ...
,
laminin
Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major constituents of the basement membrane, namely the basal lamina (the protein network foundation for most cells and organs). Laminins are vital to bi ...
,
fibulin, and
integrin
Integrins are transmembrane receptors that help cell–cell and cell–extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, o ...
.
Molecular structure
A single collagen molecule, tropocollagen, is used to make up larger collagen aggregates, such as fibrils. It is approximately 300
nm long and 1.5 nm in diameter, and it is made up of three
polypeptide
Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ...
strands (called alpha peptides, see step 2), each of which has the conformation of a left-handed
helix
A helix (; ) is a shape like a cylindrical coil spring or the thread of a machine screw. It is a type of smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as the DNA molecule is for ...
– this should not be confused with the right-handed
alpha helix
An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix).
The alpha helix is the most common structural arrangement in the Protein secondary structure, secondary structure of proteins. It is al ...
. These three left-handed helices are twisted together into a right-handed triple helix or "super helix", a cooperative
quaternary structure stabilized by many
hydrogen bond
In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...
s. With type I collagen and possibly all fibrillar collagens, if not all collagens, each triple-helix associates into a right-handed super-super-coil referred to as the collagen microfibril. Each microfibril is
interdigitated with its neighboring microfibrils to a degree that might suggest they are individually unstable, although within collagen fibrils, they are so well ordered as to be crystalline.
A distinctive feature of collagen is the regular arrangement of amino acids in each of the three chains of these collagen subunits. The sequence often follows the pattern
Gly-
Pro-X or Gly-X-
Hyp, where X may be any of various other amino acid residues.
Proline or hydroxyproline constitute about 1/6 of the total sequence. With glycine accounting for the 1/3 of the sequence, this means approximately half of the collagen sequence is not glycine, proline or hydroxyproline, a fact often missed due to the distraction of the unusual GX
1X
2 character of collagen alpha-peptides. The high glycine content of collagen is important with respect to stabilization of the collagen helix, as this allows the very close association of the collagen fibers within the molecule, facilitating hydrogen bonding and the formation of intermolecular cross-links.
This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as silk
fibroin
Fibroin is an insoluble protein present in silk produced by numerous insects, such as the larvae of ''Bombyx mori'', and other moth genera such as ''Antheraea'', ''Cricula trifenestrata, Cricula'', ''Samia (moth), Samia'' and ''Gonometa''. Sil ...
.
Collagen is not only a structural protein. Due to its key role in the determination of cell phenotype, cell adhesion, tissue regulation, and infrastructure, many sections of its non-proline-rich regions have cell or matrix association/regulation roles. The relatively high content of proline and hydroxyproline rings, with their geometrically constrained
carboxyl
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl group (e.g. ...
and (secondary)
amino groups, along with the rich abundance of glycine, accounts for the tendency of the individual polypeptide strands to form left-handed helices spontaneously, without any intrachain hydrogen bonding.
Because glycine is the smallest amino acid with no side chain, it plays a unique role in fibrous structural proteins. In collagen, Gly is required at every third position because the assembly of the triple helix puts this residue at the interior (axis) of the helix, where there is no space for a larger side group than glycine's single
hydrogen
Hydrogen is a chemical element; it has chemical symbol, symbol H and atomic number 1. It is the lightest and abundance of the chemical elements, most abundant chemical element in the universe, constituting about 75% of all baryon, normal matter ...
atom. For the same reason, the rings of the Pro and Hyp must point outward. These two amino acids help stabilize the triple helix – Hyp even more so than Pro because of a stereoelectronic effect; a lower concentration of them is required in animals such as fish, whose
body temperatures are lower than most warm-blooded animals. Lower proline and hydroxyproline contents are characteristic of cold-water, but not warm-water fish; the latter tend to have similar proline and hydroxyproline contents to mammals.
The lower proline and hydroxyproline contents of cold-water fish and other
poikilotherm
A poikilotherm () is an animal (Greek ''poikilos'' – 'various', 'spotted', and ''therme'' – 'heat') whose internal temperature varies considerably. Poikilotherms have to survive and adapt to environmental stress. One of the most important s ...
animals lead to their collagen having a lower thermal stability than mammalian collagen.
This lower thermal stability means that
gelatin
Gelatin or gelatine () is a translucent, colorless, flavorless food ingredient, commonly derived from collagen taken from animal body parts. It is brittle when dry and rubbery when moist. It may also be referred to as hydrolyzed collagen, coll ...
derived from fish collagen is not suitable for many food and industrial applications.
The tropocollagen
subunits spontaneously
self-assemble
Self-assembly is a process in which a disordered system of pre-existing components forms an organized structure or pattern as a consequence of specific, local interactions among the components themselves, without external direction. When the ...
, with regularly staggered ends, into even larger arrays in the
extracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
spaces of tissues.
Additional assembly of fibrils is guided by fibroblasts, which deposit fully formed fibrils from fibripositors. In the fibrillar collagens, molecules are staggered to adjacent molecules by about 67
nm (a unit that is referred to as 'D' and changes depending upon the hydration state of the aggregate). In each D-period repeat of the microfibril, there is a part containing five molecules in cross-section, called the "overlap", and a part containing only four molecules, called the "gap".
These overlap and gap regions are retained as microfibrils assemble into fibrils, and are thus viewable using electron microscopy. The triple helical tropocollagens in the microfibrils are arranged in a quasihexagonal packing pattern.

There is some
covalent
A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...
crosslinking within the triple helices and a variable amount of covalent crosslinking between tropocollagen helices forming well-organized aggregates (such as fibrils). Larger fibrillar bundles are formed with the aid of several different classes of proteins (including different collagen types), glycoproteins, and proteoglycans to form the different types of mature tissues from alternate combinations of the same key players.
Collagen's
insolubility was a barrier to the study of monomeric collagen until it was found that tropocollagen from young animals can be extracted because it is not yet fully
crosslinked
In chemistry and biology, a cross-link is a bond or a short sequence of bonds that links one polymer chain to another. These links may take the form of covalent bonds or ionic bonds and the polymers can be either synthetic polymers or natural ...
. However, advances in microscopy techniques (i.e. electron microscopy (EM) and atomic force microscopy (AFM)) and X-ray diffraction have enabled researchers to obtain increasingly detailed images of collagen structure ''in situ''. These later advances are particularly important to better understanding the way in which collagen structure affects cell–cell and cell–matrix communication and how tissues are constructed in growth and repair and changed in development and disease. For example, using AFM–based nanoindentation it has been shown that a single collagen fibril is a heterogeneous material along its axial direction with significantly different mechanical properties in its gap and overlap regions, correlating with its different molecular organizations in these two regions.
Collagen fibrils/aggregates are arranged in different combinations and concentrations in various tissues to provide varying tissue properties. In bone, entire collagen triple helices lie in a parallel, staggered array. 40 nm gaps between the ends of the tropocollagen subunits (approximately equal to the gap region) probably serve as nucleation sites for the deposition of long, hard, fine crystals of the mineral component, which is hydroxylapatite (approximately) Ca
10(OH)
2(PO
4)
6. Type I collagen gives bone its
tensile strength
Ultimate tensile strength (also called UTS, tensile strength, TS, ultimate strength or F_\text in notation) is the maximum stress that a material can withstand while being stretched or pulled before breaking. In brittle materials, the ultimate ...
.
Associated disorders
Collagen-related diseases most commonly arise from genetic defects or nutritional deficiencies that affect the biosynthesis, assembly, posttranslational modification, secretion, or other processes involved in normal collagen production.
In addition to the above-mentioned disorders, excessive deposition of collagen occurs in
scleroderma
Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. The disease can be either localized to the skin or involve other organs, as well. Symptoms may include areas ...
.
Diseases
One thousand mutations have been identified in 12 out of more than 20 types of collagen. These mutations can lead to various diseases at the tissue level.
Osteogenesis imperfecta
Osteogenesis imperfecta (; OI), colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that bone fracture, break easily. The range of symptoms—on the skeleton as well as on the body's other Or ...
– Caused by a mutation in ''type 1 collagen'', dominant autosomal disorder, results in weak bones and irregular connective tissue, some cases can be mild while others can be lethal. Mild cases have lowered levels of collagen type 1 while severe cases have structural defects in collagen.
Chondrodysplasias – Skeletal disorder believed to be caused by a mutation in ''type 2 collagen'', further research is being conducted to confirm this.
Ehlers–Danlos syndrome – Thirteen different types of this disorder, which lead to deformities in connective tissue, are known. Some of the rarer types can be lethal, leading to the rupture of arteries. Each syndrome is caused by a different mutation. For example, the vascular type (vEDS) of this disorder is caused by a mutation in ''collagen type 3''.
Alport syndrome – Can be passed on genetically, usually as X-linked dominant, but also as both an autosomal dominant and autosomal recessive disorder, those with the condition have problems with their kidneys and eyes, loss of hearing can also develop during the childhood or adolescent years.
Knobloch syndrome – Caused by a mutation in the
COL18A1 gene that codes for the production of collagen XVIII. Patients present with protrusion of the brain tissue and degeneration of the retina; an individual who has family members with the disorder is at an increased risk of developing it themselves since there is a hereditary link.
Animal harvesting
When not synthesized, collagen can be harvested from animal skin. This has led to deforestation as has occurred in Paraguay where large collagen producers buy large amounts of cattle hides from regions that have been
clear-cut
Clearcutting, clearfelling or clearcut logging is a forestry/logging practice in which most or all trees in an area are uniformly cut down. Along with shelterwood and seed tree harvests, it is used by foresters to create certain types of for ...
for cattle grazing.
Characteristics
Collagen is one of the long,
fibrous structural proteins whose functions are quite different from those of
globular proteins, such as
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s. Tough bundles of collagen called ''collagen fibers'' are a major component of the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...
that supports most tissues and gives cells structure from the outside, but collagen is also found inside certain cells. Collagen has great
tensile strength
Ultimate tensile strength (also called UTS, tensile strength, TS, ultimate strength or F_\text in notation) is the maximum stress that a material can withstand while being stretched or pulled before breaking. In brittle materials, the ultimate ...
, and is the main component of
fascia
A fascia (; : fasciae or fascias; adjective fascial; ) is a generic term for macroscopic membranous bodily structures. Fasciae are classified as superficial, visceral or deep, and further designated according to their anatomical location.
...
,
cartilage
Cartilage is a resilient and smooth type of connective tissue. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...
,
ligament
A ligament is a type of fibrous connective tissue in the body that connects bones to other bones. It also connects flight feathers to bones, in dinosaurs and birds. All 30,000 species of amniotes (land animals with internal bones) have liga ...
s,
tendon
A tendon or sinew is a tough band of fibrous connective tissue, dense fibrous connective tissue that connects skeletal muscle, muscle to bone. It sends the mechanical forces of muscle contraction to the skeletal system, while withstanding tensi ...
s,
bone
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...
and skin. Along with
elastin
Elastin is a protein encoded by the ''ELN'' gene in humans and several other animals. Elastin is a key component in the extracellular matrix of gnathostomes (jawed vertebrates). It is highly Elasticity (physics), elastic and present in connective ...
and soft
keratin
Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. It is the key structural material making up Scale (anatomy), scales, hair, Nail (anatomy), nails, feathers, horn (anatomy), horns, claws, Hoof, hoove ...
, it is responsible for skin strength and elasticity, and its degradation leads to
wrinkle
A wrinkle, also known as a rhytid, is a fold, ridge or crease in an otherwise smooth surface, such as on skin or fabric. Skin wrinkles typically appear as a result of ageing processes such as glycation, habitual sleeping positions, loss of b ...
s that accompany
aging
Ageing (or aging in American English) is the process of becoming Old age, older until death. The term refers mainly to humans, many other animals, and fungi; whereas for example, bacteria, perennial plants and some simple animals are potentiall ...
.
[Dermal Fillers , The Ageing Skin](_blank)
. Pharmaxchange.info. Retrieved on 21 April 2013. It strengthens
blood vessel
Blood vessels are the tubular structures of a circulatory system that transport blood throughout many Animal, animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the Tissue (biology), tissues of a Body (bi ...
s and plays a role in
tissue development. It is present in the
cornea
The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...
and lens of the eye in
crystal
A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macros ...
line form. It may be one of the most abundant proteins in the fossil record, given that it appears to fossilize frequently, even in bones from the
Mesozoic
The Mesozoic Era is the Era (geology), era of Earth's Geologic time scale, geological history, lasting from about , comprising the Triassic, Jurassic and Cretaceous Period (geology), Periods. It is characterized by the dominance of archosaurian r ...
and
Paleozoic
The Paleozoic ( , , ; or Palaeozoic) Era is the first of three Era (geology), geological eras of the Phanerozoic Eon. Beginning 538.8 million years ago (Ma), it succeeds the Neoproterozoic (the last era of the Proterozoic Eon) and ends 251.9 Ma a ...
.
Mechanical properties
Collagen is a complex hierarchical material with
mechanical properties
A material property is an intensive property of a material, i.e., a physical property or chemical property that does not depend on the amount of the material. These quantitative properties may be used as a metric by which the benefits of one mate ...
that vary significantly across different scales.
On the molecular scale,
atomistic and
course-grained modeling simulations, as well as numerous experimental methods, have led to several estimates of the
Young's modulus
Young's modulus (or the Young modulus) is a mechanical property of solid materials that measures the tensile or compressive stiffness when the force is applied lengthwise. It is the modulus of elasticity for tension or axial compression. Youn ...
of collagen at the molecular level. Only above a certain strain rate is there a strong relationship between elastic modulus and strain rate, possibly due to the large number of atoms in a collagen molecule.
The length of the molecule is also important, where longer molecules have lower tensile strengths than shorter ones due to short molecules having a large proportion of hydrogen bonds being broken and reformed.
On the
fibril
Fibrils () are structural biological materials found in nearly all living organisms. Not to be confused with fibers or protein filament, filaments, fibrils tend to have diameters ranging from 10 to 100 nanometers (whereas fibers are micro to ...
lar scale, collagen has a lower modulus compared to the molecular scale, and varies depending on geometry, scale of observation, deformation state, and hydration level.
By increasing the
crosslink density from zero to 3 per molecule, the maximum stress the fibril can support increases from 0.5 GPa to 6 GPa.
Limited tests have been done on the tensile strength of the collagen fiber, but generally it has been shown to have a lower Young's modulus compared to fibrils.
When studying the mechanical properties of collagen,
tendon
A tendon or sinew is a tough band of fibrous connective tissue, dense fibrous connective tissue that connects skeletal muscle, muscle to bone. It sends the mechanical forces of muscle contraction to the skeletal system, while withstanding tensi ...
is often chosen as the ideal material because it is close to a pure and aligned collagen structure. However, at the macro, tissue scale, the vast number of structures that collagen fibers and fibrils can be arranged into results in highly variable properties. For example, tendon has primarily parallel fibers, whereas skin consists of a net of wavy fibers, resulting in a much higher strength and lower ductility in tendon compared to skin. The mechanical properties of collagen at multiple hierarchical levels is given.
Collagen is known to be a viscoelastic solid. When the collagen fiber is modeled as two Kelvin-Voigt models in series, each consisting of a spring and a dashpot in parallel, the strain in the fiber can be modeled according to the following equation: