Collagen, type XVII, alpha 1

Last updated
COL17A1
Identifiers
Aliases COL17A1 , BA16H23.2, BP180, BPA-2, BPAG2, LAD-1, ERED, collagen type XVII alpha 1, collagen type XVII alpha 1 chain, JEB4
External IDs OMIM: 113811 HomoloGene: 133558 GeneCards: COL17A1
Orthologs
SpeciesHumanMouse
Entrez

1308

n/a

Ensembl

ENSG00000065618

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UniProt

Q9UMD9

n/a

RefSeq (mRNA)

NM_130778
NM_000494

n/a

RefSeq (protein)

NP_000485

n/a

Location (UCSC) Chr 10: 104.03 – 104.09 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

Collagen XVII, previously called BP180, is a transmembrane protein which plays a critical role in maintaining the linkage between the intracellular and the extracellular structural elements involved in epidermal adhesion, identified by Diaz and colleagues in 1990. [3] [4]

Contents

COL17A1 is the official name of the gene. It encodes the alpha chain of type XVII collagen. Collagen XVII is a transmembrane protein, like collagen XIII, XXIII and XXV. Collagen XVII is a structural component of hemidesmosomes, multiprotein complexes at the dermal-epidermal basement membrane zone that mediate adhesion of keratinocytes to the underlying membrane. It also appears to be a key protein in maintaining the integrity of the corneal epithelium. [5] Mutations in this gene are associated with both generalized atrophic benign and junctional epidermolysis bullosa, [6] as well as recurrent corneal erosions, and expression of this gene is abnormal in various cancers. [7] Two homotrimeric forms of type XVII collagen exist. The full length form is the transmembrane protein. A soluble form, referred to as either ectodomain or LAD-1, is generated by proteolytic processing of the full length form. [8]

Structure

Collagen XVII is a homotrimer of three alpha1(XVII)-chains [9] and a transmembrane protein in type II orientation. Each 180 kD a-chain contains a globular intracellular domain of approximately 70 kDa, which interacts with beta4-integrin, plectin, and BP230 [10] [11] and is necessary for the stable attachment of hemidesmosomes to keratin intermediate filaments. The large C-terminal ectodomain with a molecular mass of approximately 120 kDa consists of 15 collagenous subdomains, characterized by typical collagenous G-X-Y repeat sequences, flanked by 16 short non-collagenous stretches. The overall structure of the ectodomain is that of a flexible, rod-like triple helix [12] [13] with a significant thermal stability. [14] [15] The membrane proximal part of the ectodomain, within amino acids 506-519, is responsible for binding to alpha 6 integrin, this binding seems to be important for the collagen XVII integration into hemidesmosomes [ citation needed ]. The largest collagenous domain, Col15, which contains 232 amino acids (amino acids 567-808), contributes significantly to stability of collagen XVII homotrimer. The C-terminus of collagen XVII binds to laminin 5, and correct integration of laminin 5 into the matrix requires collagen XVII.

Pathology

Mutations in the human collagen XVII gene, COL17A1 , lead to the absence or structural alterations and mutations of collagen XVII. [16] The functional consequences include diminished epidermal adhesion and skin blistering in response to minimal shearing forces. The disorder caused by biallelic COL17A1 mutations and is called junctional epidermolysis bullosa, an autosomal recessive skin disease with variable clinical phenotypes. Morphological characteristics of junctional epidermolysis bullosa are rudimentary hemidesmosomes and subepidermal tissue separation. Clinical hallmarks, in addition to blisters and erosions of the skin and mucous membranes, include nail dystrophy, loss of hair, and dental anomalies.

Collagen XVII also plays a role as an autoantigen in Bullous pemphigoid (BP) and herpes gestationis (HG), both acquired subepithelial blistering disorders. [17] [18] Most immunodominant epitopes lie within the NC16A domain, [19] and the binding of the autoantibodies perturbs adhesive functions of the collagen XVII, and this (together with inflammation-related processes) leads to epidermal-dermal separation and skin blistering. [20]

Other mutations make the epithelium of the cornea in the eye brittle, which results in dominantly inherited recurrent corneal erosion dystrophy (ERED). Whole-exome sequencing first identified a heterozygous mutation (c.2816C>T, p.T939I) that segregated with ERED in a large Swedish pedigree dating back 200 years. [21] Another synonymous mutation (c.3156C>T) was proposed to introduce a cryptic donor site, resulting in aberrant splicing, a theory which subsequently was confirmed in several families with ERED from different countries. [5] [22]

Cancer

Expression of the COL17A1 gene is abnormal in various cancers. [7] For example, it was found abnormal in five epithelial cancer types, including breast cancer, cervical cancer, head and neck cancer and two types of lung cancer. Decreased expression was observed for breast cancer, while increased expression was observed for the other cancers. [7]

Shedding

Collagen XVII is constitutively shed from the keratinocyte surface within NC16A domain by TACE (TNF-Alpha Converting Enzyme), metalloproteinase of the ADAM family. [23] The shedding is lipid raft dependent. [24] Collagen XVII is extracellularly phosphorylated by ecto-casein kinase 2 within the NC16A domain, phosphorylation negatively regulates ectodomain shedding. [25]

SPARC and osteogenesis imperfecta

The SPARC gene is completely associated with homozygous mutations in collagen XVII, which in turn causes a type of osteogenesis imperfecta. [26] [27]

Interactions

Collagen, type XVII, alpha 1 has been shown to interact with Keratin 18, [28] Actinin alpha 4, [29] Dystonin, [11] [30] Actinin, alpha 1, [29] CTNND1 [31] and ITGB4. [32] [33]

See also

Related Research Articles

<span class="mw-page-title-main">Keratin 18</span>

Keratin 18 is a type I cytokeratin. It is, together with its filament partner keratin 8, perhaps the most commonly found products of the intermediate filament gene family. They are expressed in single layer epithelial tissues of the body. Mutations in this gene have been linked to cryptogenic cirrhosis. Two transcript variants encoding the same protein have been found for this gene.

<span class="mw-page-title-main">Hemidesmosome</span>

Hemidesmosomes are very small stud-like structures found in keratinocytes of the epidermis of skin that attach to the extracellular matrix. They are similar in form to desmosomes when visualized by electron microscopy, however, desmosomes attach to adjacent cells. Hemidesmosomes are also comparable to focal adhesions, as they both attach cells to the extracellular matrix. Instead of desmogleins and desmocollins in the extracellular space, hemidesmosomes utilize integrins. Hemidesmosomes are found in epithelial cells connecting the basal epithelial cells to the lamina lucida, which is part of the basal lamina. Hemidesmosomes are also involved in signaling pathways, such as keratinocyte migration or carcinoma cell intrusion.

<span class="mw-page-title-main">Bullous pemphigoid</span> Autoimmune disease of skin and connective tissue characterized by large blisters

Bullous pemphigoid is an autoimmune pruritic skin disease that typically occurs in people aged over 60, that may involve the formation of blisters (bullae) in the space between the epidermal and dermal skin layers. It is classified as a type II hypersensitivity reaction, which involves formation of anti-hemidesmosome antibodies, causing a loss of keratinocytes to basement membrane adhesion.

<span class="mw-page-title-main">Pemphigoid</span> Autoimmune blistering diseases

Pemphigoid is a group of rare autoimmune blistering diseases of the skin, and mucous membranes. As its name indicates, pemphigoid is similar in general appearance to pemphigus, but, unlike pemphigus, pemphigoid does not feature acantholysis, a loss of connections between skin cells.

<span class="mw-page-title-main">Keratin 5</span>

Keratin 5, also known as KRT5, K5, or CK5, is a protein that is encoded in humans by the KRT5 gene. It dimerizes with keratin 14 and forms the intermediate filaments (IF) that make up the cytoskeleton of basal epithelial cells. This protein is involved in several diseases including epidermolysis bullosa simplex and breast and lung cancers.

<span class="mw-page-title-main">Epidermolysis bullosa dystrophica</span> Medical condition

Epidermolysis bullosa dystrophica or dystrophic EB (DEB) is an inherited disease affecting the skin and other organs.

<span class="mw-page-title-main">CD151</span> Protein-coding gene in the species Homo sapiens

CD151 molecule, also known as CD151, is a human gene.

<span class="mw-page-title-main">Collagen, type VII, alpha 1</span> Protein found in humans

Collagen alpha-1(VII) chain is a protein that in humans is encoded by the COL7A1 gene. It is composed of a triple helical, collagenous domain flanked by two non-collagenous domains, and functions as an anchoring fibril between the dermal-epidermal junction in the basement membrane. Mutations in COL7A1 cause all types of dystrophic epidermolysis bullosa, and the exact mutations vary based on the specific type or subtype. It has been shown that interactions between the NC-1 domain of collagen VII and several other proteins, including laminin-5 and collagen IV, contribute greatly to the overall stability of the basement membrane.

<span class="mw-page-title-main">Integrin beta 4</span> Protein-coding gene in the species Homo sapiens

Integrin, beta 4 (ITGB4) also known as CD104, is a human gene.

<span class="mw-page-title-main">Laminin subunit gamma-2</span> Protein-coding gene in the species Homo sapiens

Laminin subunit gamma-2 is a protein that in humans is encoded by the LAMC2 gene.

<span class="mw-page-title-main">Alpha-actinin-4</span> Protein-coding gene in the species Homo sapiens

Alpha-actinin-4 is a protein that in humans is encoded by the ACTN4 gene.

<span class="mw-page-title-main">Dystonin</span> Neurologically significant human protein

Dystonin(DST), also known as bullous pemphigoid antigen 1 (BPAG1), isoforms 1/2/3/4/5/8, is a protein that in humans is encoded by the DST gene.

<span class="mw-page-title-main">Laminin, alpha 3</span> Protein-coding gene in the species Homo sapiens

Laminin subunit alpha-3 is a protein that in humans is encoded by the LAMA3 gene.

<span class="mw-page-title-main">Laminin, beta 3</span> Protein-coding gene in the species Homo sapiens

Laminin subunit beta-3 is a protein that in humans is encoded by the LAMB3 gene.

<span class="mw-page-title-main">Corneodesmosin</span> Protein-coding gene in the species Homo sapiens

Corneodesmosin is a protein that in humans is encoded by the CDSN gene.

<span class="mw-page-title-main">Collagen, type XIII, alpha 1</span> Protein found in humans

Collagen alpha-1(XIII) chain is a protein that in humans is encoded by the COL13A1 gene.

<span class="mw-page-title-main">Collagen, type XVI, alpha 1</span> Protein found in humans

Collagen alpha-1(XVI) chain is a protein that in humans is encoded by the COL16A1 gene.

<span class="mw-page-title-main">Ladinin 1</span> Protein-coding gene in the species Homo sapiens

Ladinin-1 is a protein that in humans is encoded by the LAD1 gene.

Epidermolysis bullosa acquisita, also known as acquired epidermolysis bullosa, is a longterm autoimmune blistering skin disease. It generally presents with fragile skin that blisters and becomes red with or without trauma. Marked scarring is left with thin skin, milia and nail changes. It typically begins around age 50.

<span class="mw-page-title-main">Collagen, type XXIII, alpha 1</span> Mammalian protein found in humans

Collagen α-1 (XXIII) chain is a protein encoded by COL23A1 gene, which is located on chromosome 5q35 in humans, and on chromosome 11B1+2 in mice. The location of this gene was discovered by genomic sequence analysis.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000065618 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ↑ Franzke CW, Bruckner P, Bruckner-Tuderman L (2005). "Collagenous transmembrane proteins: recent insights into biology and pathology". J. Biol. Chem. 280 (6): 4005–4008. doi: 10.1074/jbc.R400034200 . PMID   15561712.
  4. ↑ Diaz LA, Ratrie H, Saunders WS, Futamura S, Squiquera HL, Anhalt GJ, Giudice GJ (October 1990). "Isolation of a human epidermal cDNA corresponding to the 180-kD autoantigen recognized by bullous pemphigoid and herpes gestationis sera. Immunolocalization of this protein to the hemidesmosome". Journal of Clinical Investigation. 86 (4): 1088–1094. doi:10.1172/JCI114812. ISSN   0021-9738. PMC   296836 . PMID   1698819.
  5. 1 2 Oliver V, van Bysterveldt K, Cadzow M, et al. (2016). "A COL17A1 Splice-Altering Mutation Is Prevalent in Inherited Recurrent Corneal Erosions". Ophthalmology. 123 (4): 709–722. doi: 10.1016/j.ophtha.2015.12.008 . PMID   26786512.
  6. ↑ Bardhan A, Bruckner-Tuderman L, Chapple IL, Fine J, Harper N, Has C, Magin TM, Marinkovich MP, Marshall JF, McGrath JA, Mellerio JE (2020-09-24). "Epidermolysis bullosa". Nature Reviews Disease Primers. 6 (1): 78. doi:10.1038/s41572-020-0210-0. ISSN   2056-676X. PMID   32973163. S2CID   221861310.
  7. 1 2 3 Thangavelu P, Krenács T, Dray E, Duijf P (2016), "In epithelial cancers, aberrant COL17A1 promoter methylation predicts its misexpression and increased invasion", Clin Epigenetics, 8: 120, doi: 10.1186/s13148-016-0290-6 , PMC   5116176 , PMID   27891193
  8. ↑ "Entrez Gene: COL17A1 collagen, type XVII, alpha 1".
  9. ↑ Hirako Y, Usukura J, Nishizawa Y, Owaribe K (1996). "Demonstration of the molecular shape of BP180, a 180-kDa bullous pemphigoid antigen and its potential for trimer formation". J. Biol. Chem. 271 (23): 13739–13745. doi: 10.1074/jbc.271.23.13739 . PMID   8662839.
  10. ↑ Hopkinson SB, Findlay K, Jones JC, Jones JC (1998). "Interaction of BP180 (type XVII collagen) and alpha 6 integrin is necessary for stabilization of hemidesmosome structure". J. Invest. Dermatol. 111 (6): 1015–1022. doi: 10.1046/j.1523-1747.1998.00452.x . PMID   9856810.
  11. 1 2 Hopkinson SB, Jones J C (January 2000). "The N terminus of the transmembrane protein BP180 interacts with the N-terminal domain of BP230, thereby mediating keratin cytoskeleton anchorage to the cell surface at the site of the hemidesmosome". Mol. Biol. Cell. 11 (1): 277–86. doi:10.1091/mbc.11.1.277. ISSN   1059-1524. PMC   14774 . PMID   10637308.
  12. ↑ Hirako Y, Usukura J, Nishizawa Y, Owaribe K (1996). "Demonstration of the molecular shape of BP180, a 180-kDa bullous pemphigoid antigen and its potential for trimer formation". J. Biol. Chem. 271 (23): 13739–13745. doi: 10.1074/jbc.271.23.13739 . PMID   8662839.
  13. ↑ Hirako Y, Usukura J, Uematsu J, Hashimoto T, Kitajima Y, Owaribe K (1998). "Cleavage of BP180, a 180-kDa bullous pemphigoid antigen, yields a 120-kDa collagenous extracellular polypeptide". J. Biol. Chem. 273 (16): 9711–9717. doi: 10.1074/jbc.273.16.9711 . PMID   9545306.
  14. ↑ Schacke H, Schumann H, Hammami-Hauasli N, Raghunath M, Bruckner-Tuderman L (1998). "Two forms of collagen XVII in keratinocytes. A full-length transmembrane protein and a soluble ectodomain". J. Biol. Chem. 273 (40): 25937–25943. doi: 10.1074/jbc.273.40.25937 . PMID   9748270.
  15. ↑ Areida SK, Reinhardt DP, Muller PK, Fietzek PP, Kowitz J, Marinkovich MP, Notbohm H (2001). "Properties of the collagen type XVII ectodomain. Evidence for n- to c-terminal triple helix folding". J. Biol. Chem. 276 (2): 1594–1601. doi: 10.1074/jbc.M008709200 . PMID   11042218.
  16. ↑ Zillikens D, Giudice GJ (1999). "BP180/type XVII collagen: its role in acquired and inherited disorders or the dermal-epidermal junction". Arch. Dermatol. Res. 291 (4): 187–194. doi:10.1007/s004030050392. PMID   10335914. S2CID   27592712.
  17. ↑ Zillikens D (1999). "Acquired skin disease of hemidesmosomes". J. Dermatol. Sci. 20 (2): 134–154. doi:10.1016/S0923-1811(99)00019-5. PMID   10379705.
  18. ↑ Diaz LA, Ratrie H, Saunders WS, Futamura S, Squiquera HL, Anhalt GJ, Giudice GJ (October 1990). "Isolation of a human epidermal cDNA corresponding to the 180-kD autoantigen recognized by bullous pemphigoid and herpes gestationis sera. Immunolocalization of this protein to the hemidesmosome". The Journal of Clinical Investigation. 86 (4): 1088–1094. doi:10.1172/JCI114812. ISSN   0021-9738. PMC   296836 . PMID   1698819.
  19. ↑ Giudice GJ, Emery DJ, Zelickson BD, Anhalt GJ, Liu Z, Diaz LA (1993-11-15). "Bullous pemphigoid and herpes gestationis autoantibodies recognize a common non-collagenous site on the BP180 ectodomain". Journal of Immunology. 151 (10): 5742–5750. doi:10.4049/jimmunol.151.10.5742. ISSN   0022-1767. PMID   8228259.
  20. ↑ Liu Z, Diaz LA, Troy JL, Taylor AF, Emery DJ, Fairley JA, Giudice GJ (November 1993). "A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180". The Journal of Clinical Investigation. 92 (5): 2480–2488. doi:10.1172/JCI116856. ISSN   0021-9738. PMC   288433 . PMID   7693763.
  21. ↑ Jonsson F, Byström B, Davidson A, et al. (2015). "Mutations in collagen, type XVII, alpha 1 (COL17A1) cause epithelial recurrent erosion dystrophy (ERED)". Hum. Mutat. 36 (4): 463–473. doi: 10.1002/humu.22764 . PMID   25676728. S2CID   13562400.
  22. ↑ Lin B, Le D, Chem Y, et al. (2016). "Whole exome sequencing and segregation analysis confirms that a mutation in COL17A1 is the cause of epithelial recurrent erosion dystrophy in a large dominant pedigree previously mapped to chromosome 10q23-q24". PLOS ONE. 11 (6): e0157418. Bibcode:2016PLoSO..1157418L. doi: 10.1371/journal.pone.0157418 . PMC   4911149 . PMID   27309958.
  23. ↑ Franzke CW, Tasanen K, Borradori L, Huotari V, Bruckner-Tuderman L (2004). "Shedding of collagen XVII/BP180: structural motifs influence cleavage from cell surface". J. Biol. Chem. 279 (23): 24521–24529. doi: 10.1074/jbc.M308835200 . PMID   15047704.
  24. ↑ Zimina EP, Bruckner-Tuderman L, Franzke C (2005). "Shedding of collagen XVII ectodomain depends on plasma membrane microenvironment". J Biol Chem. 280 (40): 34019–24. doi: 10.1074/jbc.M503751200 . PMID   16020548.
  25. ↑ Zimina EP, Fritsch A, Schermer B, Bakulina AY, Bashkurov M, Benzing T, Bruckner-Tuderman L (2007). "Extracellular phosphorylation of collagen XVII by ecto-casein kinase 2 inhibits ectodomain shedding". J Biol Chem. 282 (31): 22737–46. doi: 10.1074/jbc.M701937200 . PMID   17545155.
  26. ↑ Reference GH. "SPARC gene". Genetics Home Reference.
  27. ↑ "OMIM Entry - # 616507 - OSTEOGENESIS IMPERFECTA, TYPE XVII; OI17". omim.org.
  28. ↑ Aho S, Uitto J (March 1999). "180-kD bullous pemphigoid antigen/type XVII collagen: tissue-specific expression and molecular interactions with keratin 18". J. Cell. Biochem. 72 (3): 356–67. doi:10.1002/(SICI)1097-4644(19990301)72:3<356::AID-JCB5>3.0.CO;2-M. ISSN   0730-2312. PMID   10022517. S2CID   30404639.
  29. 1 2 Gonzalez AM, Otey C, Edlund M, Jones J C (December 2001). "Interactions of a hemidesmosome component and actinin family members". J. Cell Sci. 114 (Pt 23): 4197–206. doi:10.1242/jcs.114.23.4197. ISSN   0021-9533. PMID   11739652.
  30. ↑ Koster J, Geerts Dirk, Favre Bertrand, Borradori Luca, Sonnenberg Arnoud (January 2003). "Analysis of the interactions between BP180, BP230, plectin and the integrin alpha6beta4 important for hemidesmosome assembly". J. Cell Sci. 116 (Pt 2): 387–99. doi:10.1242/jcs.00241. ISSN   0021-9533. PMID   12482924. S2CID   16745491.
  31. ↑ Aho S, Rothenberger K, Uitto J (June 1999). "Human p120ctn catenin: tissue-specific expression of isoforms and molecular interactions with BP180/type XVII collagen". J. Cell. Biochem. 73 (3): 390–9. doi:10.1002/(SICI)1097-4644(19990601)73:3<390::AID-JCB10>3.0.CO;2-1. ISSN   0730-2312. PMID   10321838. S2CID   43899550.
  32. ↑ Aho S, Uitto J (February 1998). "Direct interaction between the intracellular domains of bullous pemphigoid antigen 2 (BP180) and beta 4 integrin, hemidesmosomal components of basal keratinocytes". Biochem. Biophys. Res. Commun. 243 (3): 694–9. doi:10.1006/bbrc.1998.8162. ISSN   0006-291X. PMID   9500991.
  33. ↑ Schaapveld RQ, Borradori L, Geerts D, van Leusden M R, Kuikman I, Nievers M G, Niessen C M, Steenbergen R D, Snijders P J, Sonnenberg A (July 1998). "Hemidesmosome formation is initiated by the beta4 integrin subunit, requires complex formation of beta4 and HD1/plectin, and involves a direct interaction between beta4 and the bullous pemphigoid antigen 180". J. Cell Biol. 142 (1): 271–84. doi:10.1083/jcb.142.1.271. ISSN   0021-9525. PMC   2133016 . PMID   9660880.

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