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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; MGI: 88450; HomoloGene: 133558; GeneCards: COL17A1; OMA:COL17A1 - orthologs
Gene location (Human) Chr. Chromosome 10 (human) Band 10q25.1 Start 104,031,286 bp End 104,085,880 bp
Gene location (Mouse) Chr. Chromosome 19 (mouse) Band 19 D1|19 40.07 cM Start 47,634,783 bp End 47,680,533 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in skin of abdomen skin of leg skin of arm mucosa of transverse colon minor salivary glands rectum skin of thigh skin of hip olfactory zone of nasal mucosa right testis Top expressed in corneal stroma skin of external ear lip conjunctival fornix molar skin of back esophagus skin of abdomen epidermis female urethra More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding extracellular matrix structural constituent extracellular matrix structural constituent conferring tensile strength Cellular component integral component of membrane extracellular region basement membrane cell junction plasma membrane collagen integral component of plasma membrane hemidesmosome endoplasmic reticulum lumen membrane cell-cell junction extracellular space extracellular matrix collagen-containing extracellular matrix Biological process hemidesmosome assembly cell-matrix adhesion epidermis development regulation of immune response extracellular matrix organization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1308 12821 Ensembl ENSG00000065618 ENSMUSG00000025064 UniProt Q9UMD9 Q07563 RefSeq (mRNA) NM_130778 NM_000494 NM_007732 NM_001290825 RefSeq (protein) NP_000485 NP_001277754 NP_031758 Location (UCSC) Chr 10: 104.03 – 104.09 Mb Chr 19: 47.63 – 47.68 Mb PubMed search
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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.

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. Mutations in this gene are associated with both generalized atrophic benign and junctional epidermolysis bullosa, as well as recurrent corneal erosions, and expression of this gene is abnormal in various cancers. 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.

Structure

Collagen XVII is a homotrimer of three alpha1(XVII)-chains 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 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 with a significant thermal stability. 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 . 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. 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. Most immunodominant epitopes lie within the NC16A domain, 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.

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. 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.

Cancer

Expression of the COL17A1 gene is abnormal in various cancers. 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.

Shedding

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

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.

Interactions

Collagen, type XVII, alpha 1 has been shown to interact with Keratin 18, Actinin alpha 4, Dystonin, Actinin, alpha 1, CTNND1 and ITGB4.

See also

• List of target antigens in pemphigoid

References

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2. ^ GRCm38: Ensembl release 89: ENSMUSG00000025064 – Ensembl, May 2017
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6. 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.
7. ^ 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.
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9. ^ 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
10. "Entrez Gene: COL17A1 collagen, type XVII, alpha 1".
11. 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.
12. 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.
13. ^ 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. Reference GH. "SPARC gene". Genetics Home Reference.
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31. ^ 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.
32. 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.
33. 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.
34. 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.
35. 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.

Further reading

• Giudice GJ, Emery DJ, Diaz LA (1992). "Cloning and primary structural analysis of the bullous pemphigoid autoantigen BP180". J. Invest. Dermatol. 99 (3): 243–50. doi:10.1111/1523-1747.ep12616580. PMID 1324962.
• Li KH, Sawamura D, Giudice GJ, et al. (1992). "Genomic organization of collagenous domains and chromosomal assignment of human 180-kDa bullous pemphigoid antigen-2, a novel collagen of stratified squamous epithelium". J. Biol. Chem. 266 (35): 24064–9. doi:10.1016/S0021-9258(18)54393-3. PMID 1748679.
• Sawamura D, Li KH, Nomura K, et al. (1991). "Bullous pemphigoid antigen: cDNA cloning, cellular expression, and evidence for polymorphism of the human gene". J. Invest. Dermatol. 96 (6): 908–15. doi:10.1111/1523-1747.ep12475433. PMID 2045679.
• McGrath JA, Gatalica B, Christiano AM, et al. (1995). "Mutations in the 180-kD bullous pemphigoid antigen (BPAG2), a hemidesmosomal transmembrane collagen (COL17A1), in generalized atrophic benign epidermolysis bullosa". Nat. Genet. 11 (1): 83–6. doi:10.1038/ng0995-83. PMID 7550320. S2CID 23732185.
• Myers JC, Sun MJ, D'Ippolito JA, et al. (1993). "Human cDNA clones transcribed from an unusually high-molecular-weight RNA encode a new collagen chain". Gene. 123 (2): 211–7. doi:10.1016/0378-1119(93)90126-N. PMID 7916703.
• 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): 13739–45. doi:10.1074/jbc.271.23.13739. PMID 8662839.
• McGrath JA, Gatalica B, Li K, et al. (1996). "Compound heterozygosity for a dominant glycine substitution and a recessive internal duplication mutation in the type XVII collagen gene results in junctional epidermolysis bullosa and abnormal dentition". Am. J. Pathol. 148 (6): 1787–96. PMC 1861650. PMID 8669466.
• Gatalica B, Pulkkinen L, Li K, et al. (1997). "Cloning of the human type XVII collagen gene (COL17A1), and detection of novel mutations in generalized atrophic benign epidermolysis bullosa". American Journal of Human Genetics. 60 (2): 352–65. PMC 1712405. PMID 9012408.
• Jonkman MF, Scheffer H, Stulp R, et al. (1997). "Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion". Cell. 88 (4): 543–51. doi:10.1016/S0092-8674(00)81894-2. PMID 9038345. S2CID 18970859.
• Borradori L, Koch PJ, Niessen CM, et al. (1997). "The localization of bullous pemphigoid antigen 180 (BP180) in hemidesmosomes is mediated by its cytoplasmic domain and seems to be regulated by the beta4 integrin subunit". J. Cell Biol. 136 (6): 1333–47. doi:10.1083/jcb.136.6.1333. PMC 2132520. PMID 9087447.
• Schumann H, Hammami-Hauasli N, Pulkkinen L, et al. (1997). "Three novel homozygous point mutations and a new polymorphism in the COL17A1 gene: relation to biological and clinical phenotypes of junctional epidermolysis bullosa". American Journal of Human Genetics. 60 (6): 1344–53. doi:10.1086/515463. PMC 1716115. PMID 9199555.
• Chavanas S, Gache Y, Tadini G, et al. (1997). "A homozygous in-frame deletion in the collagenous domain of bullous pemphigoid antigen BP180 (type XVII collagen) causes generalized atrophic benign epidermolysis bullosa". J. Invest. Dermatol. 109 (1): 74–8. doi:10.1111/1523-1747.ep12276614. PMID 9204958.
• Darling TN, Yee C, Koh B, et al. (1998). "Cycloheximide facilitates the identification of aberrant transcripts resulting from a novel splice-site mutation in COL17A1 in a patient with generalized atrophic benign epidermolysis bullosa". J. Invest. Dermatol. 110 (2): 165–9. doi:10.1046/j.1523-1747.1998.00103.x. PMID 9457913.
• Aho S, Uitto J (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. PMID 9500991.
• Aho S, McLean WH, Li K, Uitto J (1998). "cDNA cloning, mRNA expression, and chromosomal mapping of human and mouse periplakin genes". Genomics. 48 (2): 242–7. doi:10.1006/geno.1997.5188. PMID 9521878.
• Schaapveld RQ, Borradori L, Geerts D, et al. (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. PMC 2133016. PMID 9660880.
• Ishiko A, Shimizu H, Masunaga T, et al. (1998). "97 kDa linear IgA bullous dermatosis antigen localizes in the lamina lucida between the NC16A and carboxyl terminal domains of the 180 kDa bullous pemphigoid antigen". J. Invest. Dermatol. 111 (1): 93–6. doi:10.1046/j.1523-1747.1998.00231.x. PMID 9665393.
• Floeth M, Fiedorowicz J, Schäcke H, et al. (1998). "Novel homozygous and compound heterozygous COL17A1 mutations associated with junctional epidermolysis bullosa". J. Invest. Dermatol. 111 (3): 528–33. doi:10.1046/j.1523-1747.1998.00325.x. PMID 9740252.
• Schäcke H, Schumann H, Hammami-Hauasli N, et al. (1998). "Two forms of collagen XVII in keratinocytes. A full-length transmembrane protein and a soluble ectodomain". J. Biol. Chem. 273 (40): 25937–43. doi:10.1074/jbc.273.40.25937. PMID 9748270.
• Aho S, Uitto J (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. PMID 10022517. S2CID 30404639.

• Genes on human chromosome 10
• Collagens