Collagen, type XVII, alpha 1

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, , 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.2816CT, p.T939I) that segregated with ERED in a large Swedish pedigree dating back 200 years. Another synonymous mutation (c.3156CT) 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.

References

References

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3. (April 2016). "A COL17A1 Splice-Altering Mutation Is Prevalent in Inherited Recurrent Corneal Erosions". Ophthalmology.
4. (September 2020). "Epidermolysis bullosa". Nature Reviews. Disease Primers.
5. (2016). "In epithelial cancers, aberrant COL17A1 promoter methylation predicts its misexpression and increased invasion". Clinical Epigenetics.
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8. (December 1998). "Interaction of BP180 (type XVII collagen) and alpha6 integrin is necessary for stabilization of hemidesmosome structure". The Journal of Investigative Dermatology.
9. (June 1996). "Demonstration of the molecular shape of BP180, a 180-kDa bullous pemphigoid antigen and its potential for trimer formation". The Journal of Biological Chemistry.
10. (April 1998). "Cleavage of BP180, a 180-kDa bullous pemphigoid antigen, yields a 120-kDa collagenous extracellular polypeptide". The Journal of Biological Chemistry.
11. (October 1998). "Two forms of collagen XVII in keratinocytes. A full-length transmembrane protein and a soluble ectodomain". The Journal of Biological Chemistry.
12. (January 2001). "Properties of the collagen type XVII ectodomain. Evidence for n- to c-terminal triple helix folding". The Journal of Biological Chemistry.
13. (April 1999). "BP180/type XVII collagen: its role in acquired and inherited disorders or the dermal-epidermal junction". Archives of Dermatological Research.
14. (June 1999). "Acquired skin disease of hemidesmosomes". Journal of Dermatological Science.
15. (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.
16. (November 1993). "Bullous pemphigoid and herpes gestationis autoantibodies recognize a common non-collagenous site on the BP180 ectodomain". Journal of Immunology.
17. (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.
18. (April 2015). "Mutations in collagen, type XVII, alpha 1 (COL17A1) cause epithelial recurrent erosion dystrophy (ERED)". Human Mutation.
19. (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.
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21. (October 2005). "Shedding of collagen XVII ectodomain depends on plasma membrane microenvironment". The Journal of Biological Chemistry.
22. (August 2007). "Extracellular phosphorylation of collagen XVII by ecto-casein kinase 2 inhibits ectodomain shedding". The Journal of Biological Chemistry.
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27. (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". Molecular Biology of the Cell.
28. (January 2003). "Analysis of the interactions between BP180, BP230, plectin and the integrin alpha6beta4 important for hemidesmosome assembly". Journal of Cell Science.
29. (June 1999). "Human p120ctn catenin: tissue-specific expression of isoforms and molecular interactions with BP180/type XVII collagen". Journal of Cellular Biochemistry.
30. (February 1998). "Direct interaction between the intracellular domains of bullous pemphigoid antigen 2 (BP180) and beta 4 integrin, hemidesmosomal components of basal keratinocytes". Biochemical and Biophysical Research Communications.
31. (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". The Journal of Cell Biology.