Filaggrin (filament aggregating protein) is a filament-associated

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 ...

that binds to

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 ...

fibers in

epithelial cell Epithelium or epithelial tissue is a thin, continuous, protective layer of Cell (biology), cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial (Mesothelium, mesothelial) tissues line ...

s. Ten to twelve filaggrin units are post-translationally hydrolyzed from a large profilaggrin precursor protein during

terminal differentiation Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...

of epidermal cells. In humans, profilaggrin is encoded by the ''FLG'' gene, which is part of the

S100 fused-type protein The epidermal differentiation complex (EDC) is a gene complex comprising over fifty genes encoding proteins involved in the terminal Cellular differentiation, differentiation and cornification of keratinocytes, the primary cell type of the epidermi ...

(SFTP) family within the

epidermal differentiation complex The epidermal differentiation complex (EDC) is a gene complex comprising over fifty genes encoding proteins involved in the terminal Cellular differentiation, differentiation and cornification of keratinocytes, the primary cell type of the epidermi ...

chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which a ...

q21. In

cetaceans Cetacea (; , ) is an infraorder of aquatic mammals belonging to the order Artiodactyla that includes whales, dolphins and porpoises. Key characteristics are their fully aquatic lifestyle, streamlined body shape, often large size and exclusively c ...

and

sirenians The Sirenia (), commonly referred to as sea cows or sirenians, are an order (biology), order of fully aquatic, herbivorous mammals that inhabit swamps, rivers, estuaries, marine wetlands, and coastal marine waters. The extant Sirenia comprise tw ...

, the ''FLG'' family has lost its function, with the curious exception of

manatees Manatees (, family Trichechidae, genus ''Trichechus'') are large, fully aquatic, mostly herbivorous marine mammals sometimes known as sea cows. There are three accepted living species of Trichechidae, representing three of the four living spe ...

in the latter

clade In biology, a clade (), also known as a Monophyly, monophyletic group or natural group, is a group of organisms that is composed of a common ancestor and all of its descendants. Clades are the fundamental unit of cladistics, a modern approach t ...

: manatees still retain some functional ''FLG'' genes.

Profilaggrin

Filaggrin monomers are tandemly clustered into a large, 350kDa protein precursor known as profilaggrin. In the

epidermis The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and Subcutaneous tissue, hypodermis. The epidermal layer provides a barrier to infection from environmental pathogens and regulates the ...

, these structures are present in the keratohyalin granules in cells of the

stratum granulosum The stratum granulosum (or granular layer) is a thin layer of cells in the epidermis lying above the stratum spinosum and below the stratum corneum ( stratum lucidum on the soles and palms).James, William; Berger, Timothy; Elston, Dirk (2005) ''A ...

. Profilaggrin undergoes

proteolytic Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...

processing to yield individual filaggrin monomers at the transition between the stratum granulosum and the

stratum corneum The stratum corneum (Latin language, Latin for 'horny layer') is the outermost layer of the epidermis (skin), epidermis. Consisting of dead tissue, it protects underlying tissue from infection, dehydration, chemicals and mechanical stress. It is ...

, which may be facilitated by

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 ...

-dependent

enzymes An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as pro ...

Structure

Filaggrin is characterized by a particularly high

isoelectric point The isoelectric point (pI, pH(I), IEP), is the pH at which a molecule carries no net electric charge, electrical charge or is electrically neutral in the statistical mean. The standard nomenclature to represent the isoelectric point is pH(I). Howe ...

due to the relatively high presence of

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...

in its primary structure. It is also relatively low in the

sulfur Sulfur ( American spelling and the preferred IUPAC name) or sulphur ( Commonwealth spelling) is a chemical element; it has symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms ...

-containing amino acids

methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other non-essential amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine play ...

and

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

Function

Filaggrin is essential for the regulation of epidermal

homeostasis In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...

. Within the

, filaggrin monomers can become incorporated into the

lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...

envelope, which is responsible for the skin barrier function. Alternatively, these proteins can interact with keratin

intermediate filaments Intermediate filaments (IFs) are cytoskeletal structural components found in the cells of vertebrates, and many invertebrates. Homologues of the IF protein have been noted in an invertebrate, the cephalochordate ''Branchiostoma''. Intermedi ...

. Filaggrin undergoes further processing in the upper stratum corneum to release free

amino acids 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 Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

that assist in water retention. Some studies attribute an important role to filaggrin in maintaining the physiological acidic pH of the skin, through a breaking-down mechanism to form histidine and subsequently trans-

urocanic acid Urocanic acid (formally ''trans''-Urocanic acid) is an intermediate in the catabolism of L-histidine. The cis-urocanic acid, ''cis''-urocanic acid isomer is rare. Metabolism It is formed from L-histidine through the action of histidine ammonialyas ...

. However, others have shown that the filaggrin–histidine–urocanic acid cascade is not essential for skin acidification.

Clinical significance

Individuals with truncation

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

s in the

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

coding for filaggrin are strongly predisposed to a severe form of dry skin, ichthyosis vulgaris, and/or

eczema Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened ...

. It has been shown that almost 50% of all severe cases of eczema may have at least one mutated filaggrin gene. R501X and 2284del4 are not generally found in non-Caucasian individuals, though novel mutations (3321delA and S2554X) that yield similar effects have been found in Japanese populations. Truncation mutations R501X and 2284del4 are the most common mutations in the Caucasian population, with 7 to 10% of the Caucasian population carrying at least one copy of these mutations.

Autoantibodies An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies. Pr ...

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

recognizing an

epitope An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that binds to the epitope is called a paratope. Although e ...

of citrullinated peptides are cross-reactive with filaggrin. The barrier defect seen in filaggrin null carriers also appears to lead to increased

asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...

susceptibility and exacerbations. Filaggrin deficiency is one of the top genome-wide genetic determinants of asthma, along with the variants found that regulate ORMDL3 expression. In early infancy, the

penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the pr ...

of filaggrin mutations may be increased by household exposure to cats.

References

External links