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 ^[1]. Image File history File links Information_icon. ...

Collagen XVII is a homotrimer of three alpha1(XVII)-chains ^[2] and a transmembrane protein in type II orientation. Each 180 kD a-chain contains an globular intracellular domain of approximately 70 kDa, which interacts with beta4-integrin, plectin, and BP230 ^[3][4] 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 ^{[5] [6]} with a significant thermal stability ^[7][8]. 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. Tropocollagen triple helix. ... An integrin, or integrin receptor, is an integral membrane protein in the plasma membrane of cells. ... A giant protein (c500 kDa) which binds actin, microtubules and intermediate filaments. ... Hemidesmosomes (HD) are very small stud- or rivet-like structures on the inner basal surface of keratinocytes in the epidermis of skin. ... Microscopy of keratin filaments inside cells. ...

Mutations in the human collagen XVII gene, COL17A1, lead to the absence or structural alterations of collagen XVII ^[9]. The functional consequences include diminished epidermal adhesion and skin blistering in response to minimal shearing forces . The disorder 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 acquired subepithelial blistering disorders ^[10]. 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.

Collagen XVII is constitutively shed from the keratinocyte surface within NC16A domain by TACE (TNF-Alpha Converting Enzyme), metalloproteinase of the ADAM family ^[11]. The shedding is lipid raft dependent ^[12]. Collagen XVII is extracellularly phosphorylated by ecto-casein kinase 2 within the NC16A domain, phosphorylation negatively regulates ectodomain shedding.

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References

1. ^ Franzke, C. W., Bruckner, P., and Bruckner-Tuderman, L. (2005) Collagenous transmembrane proteins: recent insights into biology and pathology. J.Biol.Chem. 280: 4005-4008
2. ^ Hirako, Y., Usukura, J., Nishizawa, Y., and 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: 13739-13745
3. ^ Hopkinson, S. B., Findlay, K., deHart, G. W., and Jones, J. C. (1998) Interaction of BP180 (type XVII collagen) and alpha 6 integrin is necessary for stabilization of hemidesmosome structure. J.Invest Dermatol. 111: 1015-1022
4. ^ Hopkinson, S. B. and Jones, J. C. (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: 277-286
5. ^ Hirako, Y., Usukura, J., Nishizawa, Y., and 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: 13739-13745
6. ^ Hirako, Y., Usukura, J., Uematsu, J., Hashimoto, T., Kitajima, Y., and Owaribe, K. (1998) Cleavage of BP180, a 180-kDa bullous pemphigoid antigen, yields a 120-kDa collagenous extracellular polypeptide. J.Biol.Chem. 273: 9711-9717
7. ^ Schacke, H., Schumann, H., Hammami-Hauasli, N., Raghunath, M., and Bruckner-Tuderman, L. (1998) Two forms of collagen XVII in keratinocytes. A full-length transmembrane protein and a soluble ectodomain. J.Biol.Chem. 273: 25937-25943
8. ^ Areida, S. K., Reinhardt, D. P., Muller, P. K., Fietzek, P. P., Kowitz, J., Marinkovich, M. P., and Notbohm, H. (2001) Properties of the collagen type XVII ectodomain. Evidence for n- to c-terminal triple helix folding. J.Biol.Chem. 276: 1594-1601
9. ^ Zillikens, D. and Giudice, G. J. (1999) BP180/type XVII collagen: its role in acquired and inherited disorders or the dermal-epidermal junction. Arch Dermatol.Res 291: 187-194
10. ^ Zillikens, D. (1999) Acquired skin disease of hemidesmosomes. J.Dermatol.Sci. 20: 134-154
11. ^ Franzke, C. W., Tasanen, K., Borradori, L., Huotari, V., and Bruckner-Tuderman, L. (2004) Shedding of collagen XVII/BP180: structural motifs influence cleavage from cell surface. J.Biol.Chem. 279: 24521-24529
12. ^ Zimina EP, Bruckner-Tuderman L, Franzke CW. (2005). Shedding of collagen XVII ectodomain depends on plasma membrane microenvironment. J Biol Chem. 280(40):34019-24.