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The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most
eukaryotic cells Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
and forms an interconnected network of flattened, membrane-enclosed sacs known as
cisterna A cisterna (plural cisternae) is a flattened membrane vesicle found in the endoplasmic reticulum and Golgi apparatus. Cisternae are an integral part of the packaging and modification processes of proteins occurring in the Golgi. Function Protei ...
e (in the RER), and tubular structures in the SER. The membranes of the ER are continuous with the outer nuclear membrane. The endoplasmic reticulum is not found in
red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "hol ...
s, or
spermatozoa A spermatozoon (; also spelled spermatozoön; ; ) is a motile sperm cell, or moving form of the haploid cell that is the male gamete. A spermatozoon joins an ovum to form a zygote. (A zygote is a single cell, with a complete set of chromos ...
. The two types of ER share many of the same
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s and engage in certain common activities such as the synthesis of certain
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids in ...
s and
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell memb ...
. Different types of
cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
contain different ratios of the two types of ER depending on the activities of the cell. RER is found mainly toward the nucleus of cell and SER towards the cell membrane or plasma membrane of cell. The outer ( cytosolic) face of the RER is studded with ribosomes that are the sites of protein synthesis. The RER is especially prominent in cells such as
hepatocyte A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, ...
s. The SER lacks ribosomes and functions in
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids in ...
synthesis but not
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...
, the production of steroid hormones, and
detoxification Detoxification or detoxication (detox for short) is the physiological or medicinal removal of toxic substances from a living organism, including the human body, which is mainly carried out by the liver. Additionally, it can refer to the period of ...
. The SER is especially abundant in mammalian
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
and gonad cells. The ER was observed with light microscope by Garnier in 1897, who coined the term ''ergastoplasm''. With electron microscopy, the lacy membranes of the endoplasmic reticulum were first seen in 1945 by
Keith R. Porter Keith Roberts Porter (June 11, 1912 – May 2, 1997) was a Canadian- American cell biologist. He created pioneering biology techniques and research using electron microscopy of cells. Porter also contributed to the development of other experimen ...
, Albert Claude, and Ernest F. Fullam. Later, the word '' reticulum'', which means "network", was applied by Porter in 1953 to describe this fabric of membranes.


Structure

The general structure of the endoplasmic reticulum is a network of membranes called
cisterna A cisterna (plural cisternae) is a flattened membrane vesicle found in the endoplasmic reticulum and Golgi apparatus. Cisternae are an integral part of the packaging and modification processes of proteins occurring in the Golgi. Function Protei ...
e. These sac-like structures are held together by the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is co ...
. The phospholipid membrane encloses the cisternal space (or lumen), which is continuous with the perinuclear space but separate from the cytosol. The functions of the endoplasmic reticulum can be summarized as the synthesis and export of proteins and membrane lipids, but varies between ER and cell type and cell function. The quantity of both rough and smooth endoplasmic reticulum in a cell can slowly interchange from one type to the other, depending on the changing metabolic activities of the cell. Transformation can include embedding of new proteins in membrane as well as structural changes. Changes in protein content may occur without noticeable structural changes.


Rough endoplasmic reticulum

The surface of the rough endoplasmic reticulum (often abbreviated ''RER'' or ''rough ER''; also called ''granular endoplasmic reticulum'') is studded with protein-manufacturing ribosomes giving it a "rough" appearance (hence its name). The binding site of the ribosome on the rough endoplasmic reticulum is the translocon. However, the ribosomes are not a stable part of this organelle's structure as they are constantly being bound and released from the membrane. A ribosome only binds to the RER once a specific protein-nucleic acid complex forms in the cytosol. This special complex forms when a free ribosome begins translating the
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...
of a protein destined for the secretory pathway. The first 5–30
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
s polymerized encode a signal peptide, a molecular message that is recognized and bound 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 memb ...
(SRP). Translation pauses and the ribosome complex binds to the RER translocon where translation continues with the
nascent Nascent may refer to: * '' Nascent'', a 2005 Australian dance film with choreography by Garry Stewart * '' Nascent (film)'', a 2016 Central African short documentary film by Lindsay Branham and Jon Kasbe See also * * * Nascent hydrogen, disc ...
(new) protein forming into the RER lumen and/or membrane. The protein is processed in the ER lumen by an enzyme (a signal peptidase), which removes the signal peptide. Ribosomes at this point may be released back into the cytosol; however, non-translating ribosomes are also known to stay associated with translocons. The membrane of the rough endoplasmic reticulum forms large double-membrane sheets that are located near, and continuous with, the outer layer of the nuclear envelope. The double membrane sheets are stacked and connected through several right- or left-handed helical ramps, the "Terasaki ramps", giving rise to a structure resembling a parking garage. Although there is no continuous membrane between the endoplasmic reticulum and 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 cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...
, membrane-bound transport vesicles shuttle proteins between these two compartments. Vesicles are surrounded by coating proteins called COPI and COPII.
COPII The Coat Protein Complex II, or COPII, is a group of proteins that facilitate the formation of vesicles to transport proteins from the endoplasmic reticulum to the Golgi apparatus or endoplasmic-reticulum–Golgi intermediate compartment. This ...
targets vesicles to the Golgi apparatus and COPI marks them to be brought back to the rough endoplasmic reticulum. The rough endoplasmic reticulum works in concert with the Golgi complex to target new proteins to their proper destinations. The second method of transport out of the endoplasmic reticulum involves areas called membrane contact sites, where the membranes of the endoplasmic reticulum and other organelles are held closely together, allowing the transfer of lipids and other small molecules. The rough endoplasmic reticulum is key in multiple functions: * Manufacture of lysosomal enzymes with a mannose-6-phosphate marker added in the ''cis''-Golgi network. * Manufacture of secreted proteins, either secreted constitutively with no tag or secreted in a regulatory manner involving clathrin and paired basic amino acids in the signal peptide. * Integral membrane proteins that stay embedded in the membrane as vesicles exit and bind to new membranes.
Rab Rab �âːb( dlm, Arba, la, Arba, it, Arbe, german: Arbey) is an island in the northern Dalmatia region in Croatia, located just off the northern Croatian coast in the Adriatic Sea. The island is long, has an area of and 9,328 inhabitants (2 ...
proteins are key in targeting the membrane; SNAP and SNARE proteins are key in the fusion event. * Initial glycosylation as assembly continues. This is N-linked (O-linking occurs in the Golgi). ** N-linked glycosylation: If the protein is properly folded, oligosaccharyltransferase recognizes the AA sequence NX S or NX T (with the S/T residue phosphorylated) and adds a 14-sugar backbone (2-''N''-acetylglucosamine, 9-branching
mannose Mannose is a sugar monomer of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylation of certain proteins. Several congenital disorders of glycosylat ...
, and 3-
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
at the end) to the side-chain
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
of Asn.


Smooth endoplasmic reticulum

In most cells the smooth endoplasmic reticulum (abbreviated SER) is scarce. Instead there are areas where the ER is partly smooth and partly rough, this area is called the transitional ER. The transitional ER gets its name because it contains ER exit sites. These are areas where the transport vesicles that contain lipids and proteins made in the ER, detach from the ER and start moving 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 cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...
. Specialized cells can have a lot of smooth endoplasmic reticulum and in these cells the smooth ER has many functions. It synthesizes
lipids Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids in ...
,
phospholipids Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids ...
, and
steroids A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
. Cells which secrete these products, such as those in the testes,
ovaries The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
, and
sebaceous gland A sebaceous gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur in the greatest n ...
s have an abundance of smooth endoplasmic reticulum. It also carries out the metabolism of carbohydrates, detoxification of natural metabolism products and of alcohol and drugs, attachment of receptors on cell membrane proteins, and steroid metabolism. In muscle cells, it regulates calcium ion concentration. Smooth endoplasmic reticulum is found in a variety of cell types (both animal and plant), and it serves different functions in each. The smooth endoplasmic reticulum also contains the enzyme
glucose-6-phosphatase The enzyme glucose 6-phosphatase (EC 3.1.3.9, G6Pase; systematic name D-glucose-6-phosphate phosphohydrolase) catalyzes the hydrolysis of glucose 6-phosphate, resulting in the creation of a phosphate group and free glucose: : D-glucose 6-phos ...
, which converts glucose-6-phosphate to glucose, a step in gluconeogenesis. It is connected to the nuclear envelope and consists of tubules that are located near the cell periphery. These tubes sometimes branch forming a network that is reticular in appearance. In some cells, there are dilated areas like the sacs of rough endoplasmic reticulum. The network of smooth endoplasmic reticulum allows for an increased surface area to be devoted to the action or storage of key enzymes and the products of these enzymes.


Sarcoplasmic reticulum

The sarcoplasmic reticulum (SR), from the Greek σάρξ ''sarx'' ("flesh"), is smooth ER found in muscle cells. The only structural difference between this organelle and the smooth endoplasmic reticulum is the composition of proteins they have, both bound to their membranes and drifting within the confines of their lumens. This fundamental difference is indicative of their functions: The endoplasmic reticulum synthesizes molecules, while the sarcoplasmic reticulum stores calcium ions and pumps them out into the sarcoplasm when the muscle fiber is stimulated. After their release from the sarcoplasmic reticulum, calcium ions interact with contractile proteins that utilize ATP to shorten the muscle fiber. The sarcoplasmic reticulum plays a major role in excitation-contraction coupling.


Functions

The endoplasmic reticulum serves many general functions, including the folding of protein molecules in sacs called
cisterna A cisterna (plural cisternae) is a flattened membrane vesicle found in the endoplasmic reticulum and Golgi apparatus. Cisternae are an integral part of the packaging and modification processes of proteins occurring in the Golgi. Function Protei ...
e and the transport of synthesized proteins in
vesicles Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features o ...
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 cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...
. Rough endoplasmic reticulum is also involved in protein synthesis. Correct folding of newly made proteins is made possible by several endoplasmic reticulum chaperone proteins, including protein disulfide isomerase (PDI), ERp29, the
Hsp70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an import ...
family member BiP/Grp78,
calnexin Calnexin (CNX) is 67kDaintegral protein (that appears variously as a 90kDa, 80kDa, or 75kDa band on western blotting depending on the source of the antibody) of the endoplasmic reticulum (ER). It consists of a large (50 kDa) N-terminal calcium- ...
, calreticulin, and the peptidylprolyl isomerase family. Only properly folded proteins are transported from the rough ER to the Golgi apparatus – unfolded proteins cause an unfolded protein response as a stress response in the ER. Disturbances in
redox Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or ...
regulation, calcium regulation, glucose deprivation, and viral infection or the over-expression of proteins can lead to endoplasmic reticulum stress response (ER stress), a state in which the folding of proteins slows, leading to an increase in unfolded proteins. This stress is emerging as a potential cause of damage in hypoxia/ischemia, insulin resistance, and other disorders.


Protein transport

Secretory proteins, mostly glycoproteins, are moved across the endoplasmic reticulum membrane. Proteins that are transported by the endoplasmic reticulum throughout the cell are marked with an address tag called a signal sequence. The N-terminus (one end) of a polypeptide chain (i.e., a protein) contains a few
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
s that work as an address tag, which are removed when the polypeptide reaches its destination. Nascent peptides reach the ER via the translocon, a membrane-embedded multiprotein complex. Proteins that are destined for places outside the endoplasmic reticulum are packed into transport vesicles and moved along the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is co ...
toward their destination. In human fibroblasts, the ER is always co-distributed with microtubules and the depolymerisation of the latter cause its co-aggregation with mitochondria, which are also associated with the ER. The endoplasmic reticulum is also part of a protein sorting pathway. It is, in essence, the transportation system of the eukaryotic cell. The majority of its resident proteins are retained within it through a retention motif. This motif is composed of four amino acids at the end of the protein sequence. The most common retention sequences are KDEL for lumen located proteins and KKXX for transmembrane protein. However, variations of KDEL and KKXX do occur, and other sequences can also give rise to endoplasmic reticulum retention. It is not known whether such variation can lead to sub-ER localizations. There are three KDEL ( 1, 2 and 3) receptors in mammalian cells, and they have a very high degree of sequence identity. The functional differences between these receptors remain to be established.


Bioenergetics regulation of ER ATP supply by a CaATiER mechanism

The endoplasmic reticulum does not harbor an ATP-regeneration machinery, and therefore requires ATP import from mitochondria. The imported ATP is vital for the ER to carry out its house keeping cellular functions, such as for protein folding and trafficking. The ER ATP transporter, SLC35B1/AXER, was recently cloned and characterized, and the mitochondria supply ATP to the ER through a ''Ca2+-antagonized transport into the ER'' (''CaATiER'') mechanism. The ''CaATiER'' mechanism shows sensitivity to cytosolic Ca2+ ranging from high nM to low μM range, with the Ca2+-sensing element yet to be identified and validated.


Clinical significance

Increased and supraphysiological ER stress in pancreatic β cells disrupts normal insulin secretion, leading to hyperinsulinemia and consequently peripheral insulin resistance associated with obesity in humans. Human clinical trials also suggested a causal link between obesity-induced increase in insulin secretion and peripheral insulin resistance. Abnormalities in XBP1 lead to a heightened endoplasmic reticulum stress response and subsequently causes a higher susceptibility for inflammatory processes that may even contribute to Alzheimer's disease. In the colon, XBP1 anomalies have been linked to the inflammatory bowel diseases including Crohn's disease. The unfolded protein response (UPR) is a
cellular stress response Cellular stress response is the wide range of molecular changes that cells undergo in response to environmental stressors, including extremes of temperature, exposure to toxins, and mechanical damage. Cellular stress responses can also be caused by ...
related to the endoplasmic reticulum. The UPR is activated in response to an accumulation of unfolded or misfolded
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s in the lumen of the endoplasmic reticulum. The UPR functions to restore normal function of the cell by halting protein
translation Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
, degrading misfolded proteins, and activating the signaling pathways that lead to increasing the production of molecular chaperones involved in
protein folding Protein folding is the physical process by which a protein chain is translated to its native three-dimensional structure, typically a "folded" conformation by which the protein becomes biologically functional. Via an expeditious and reproduc ...
. Sustained overactivation of the UPR has been implicated in prion diseases as well as several other neurodegenerative diseases and the inhibition of the UPR could become a treatment for those diseases.


References


External links


Endoplasmic Reticulum

Lipid and protein composition of Endoplasmic reticulum
in OPM database
Animations of the various cell functions referenced here
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