Jump to content

Filaggrin

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Michael Ly (talk | contribs) at 00:32, 28 November 2016 (S-100 link). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

FLG
Available structures
PDBHuman UniProt search: PDBe RCSB
Identifiers
AliasesFLG, ATOD2, filaggrin
External IDsOMIM: 135940; HomoloGene: 136751; GeneCards: FLG; OMA:FLG - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2312

n/a

Ensembl

ENSG00000143631

n/a

UniProt

P20930

n/a

RefSeq (mRNA)

NM_002016

n/a

RefSeq (protein)

NP_002007

n/a

Location (UCSC)Chr 1: 152.3 – 152.33 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Filaggrin (filament aggregating protein) is a filament-associated protein that binds to keratin fibers in epithelial cells. Ten to twelve filaggrin units are post-translationally hydrolized from a large profilaggrin precursor protein during terminal differentiation of epidermal cells.[3] In humans, profilaggrin is encoded by the FLG gene, which is part of the S100 fused-type protein (SFTP) family within the epidermal differentiation complex on chromosome 1q21.[4]

Profilaggrin

Filaggrin monomers are tandemly clustered into a large, 350kDa protein precursor known as profilaggrin. In the epidermis, these structures are present in the keratohyalin granules in cells of the stratum granulosum. Profilaggrin undergoes proteolytic processing to yield individual filaggrin monomers at the transition between the stratum granulosum and the stratum corneum, which may be facilitated by calcium-dependent enzymes.[5]

Structure

Filaggrin is characterized by a particularly high pH, due to a relatively high presence of histidine in its primary structure.[6] It is also relatively low in the sulfur-containing amino acids methionine and cysteine.

Function

Filaggrin is essential for the regulation of epidermal homeostasis. Within the stratum corneum, filaggrin monomers can become incorporated into the lipid envelope, which is responsible for the skin barrier function. Alternatively, these proteins can interact with keratin intermediate filaments. Filaggrin undergoes further processing in the upper stratum corneum to release free amino acids that assist in water retention.[5]

Clinical significance

Individuals with truncation mutations in the gene coding for filaggrin are strongly predisposed to a severe form of dry skin, ichthyosis vulgaris, and/or eczema.[7]

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.[8] 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.[9]

Autoantibodies in rheumatoid arthritis recognizing an epitope of citrullinated peptides are cross-reactive with filaggrin.[10]

The barrier defect seen in filaggrin null carriers also appears to lead to increased asthma susceptibility and exacerbations.[11][12][13] Filaggrin deficiency is one of the top genome-wide genetic determinants of asthma, along with the variants found that regulate ORMDL3 expression.[14]

In early infancy, the penetrance of filaggrin mutations may be increased by household exposure to cats.[15]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000143631 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ Markova, NG; Marekov, LN; Chipev, CC; Gan, SQ; Idler, WW; Steinert, PM (January 1993). "Profilaggrin is a major epidermal calcium-binding protein". Molecular and Cellular Biology. 13 (1): 613–25. doi:10.1128/MCB.13.1.613. PMC 358940. PMID 8417356.
  4. ^ Kypriotou, Magdalini; Huber, Marcel; Hohl, Daniel (September 2012). "The human epidermal differentiation complex: cornified envelope precursors, S100 proteins and the 'fused genes' family". Experimental Dermatology. 21 (9): 643–649. doi:10.1111/j.1600-0625.2012.01472.x.
  5. ^ a b Ovaere P, Lippens S, Vandenabeele P, Declercq W (September 2009). "The emerging roles of serine protease cascades in the epidermis". Trends Biochem. Sci. 34 (9): 453–63. doi:10.1016/j.tibs.2009.08.001. PMID 19726197.
  6. ^ Harding, CR; Scott, IR (5 November 1983). "Histidine-rich proteins (filaggrins): structural and functional heterogeneity during epidermal differentiation". Journal of Molecular Biology. 170 (3): 651–73. doi:10.1016/s0022-2836(83)80126-0. PMID 6195345.
  7. ^ Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A, Klopp N, Wagenpfeil S, Zhao Y, Liao H, Lee SP, Palmer CN, Jenneck C, Maintz L, Hagemann T, Behrendt H, Ring J, Nothen MM, McLean WH, Novak N (July 2006). "Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations". J. Allergy Clin. Immunol. 118 (1): 214–9. doi:10.1016/j.jaci.2006.05.004. PMID 16815158.
  8. ^ Nomura T, Sandilands A, Akiyama M, Liao H, Evans AT, Sakai K, Ota M, Sugiura H, Yamamoto K, Sato H, Palmer CN, Smith FJ, McLean WH, Shimizu H (February 2007). "Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis". J. Allergy Clin. Immunol. 119 (2): 434–40. doi:10.1016/j.jaci.2006.12.646. PMID 17291859.
  9. ^ Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O'Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH (April 2006). "Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis". Nat. Genet. 38 (4): 441–6. doi:10.1038/ng1767. PMID 16550169.
  10. ^ Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ (January 1998). "Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies". J. Clin. Invest. 101 (1): 273–81. doi:10.1172/JCI1316. PMC 508564. PMID 9421490.
  11. ^ Basu K, Palmer CN, Lipworth BJ, Irwin McLean WH, Terron-Kwiatkowski A, Zhao Y, Liao H, Smith FJ, Mitra A, Mukhopadhyay S (2008). "Filaggrin null mutations are associated with increased asthma exacerbations in children and young adults". Allergy. 63 (9): 1211–7. doi:10.1111/j.1398-9995.2008.01660.x. PMID 18307574.
  12. ^ Palmer CN, Ismail T, Lee SP, Terron-Kwiatkowski A, Zhao Y, Liao H, Smith FJ, McLean WH, Mukhopadhyay S (July 2007). "Filaggrin null mutations are associated with increased asthma severity in children and young adults". J. Allergy Clin. Immunol. 120 (1): 64–8. doi:10.1016/j.jaci.2007.04.001. PMID 17531295.
  13. ^ Henderson J, Northstone K, Lee SP, Liao H, Zhao Y, Pembrey M, Mukhopadhyay S, Smith GD, Palmer CN, McLean WH, Irvine AD (April 2008). "The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study". J. Allergy Clin. Immunol. 121 (4): 872–7.e9. doi:10.1016/j.jaci.2008.01.026. PMID 18325573.
  14. ^ Tavendale R, Macgregor DF, Mukhopadhyay S, Palmer CN (April 2008). "A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications". J. Allergy Clin. Immunol. 121 (4): 860–3. doi:10.1016/j.jaci.2008.01.015. PMID 18395550.
  15. ^ Bisgaard H, Simpson A, Palmer CN, Bønnelykke K, McLean I, Mukhopadhyay S, Pipper CB, Halkjaer LB, Lipworth B, Hankinson J, Woodcock A, Custovic A (June 2008). "Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure". PLoS Med. 5 (6): e131. doi:10.1371/journal.pmed.0050131. PMC 2504043. PMID 18578563.{{cite journal}}: CS1 maint: unflagged free DOI (link)
Retrieved from "https://en.wikipedia.org/w/index.php?title=Filaggrin&oldid=751818567"