title: The cysteine-rich domain of snake venom metalloproteinases is a ligand for von Willebrand factor A domains: role in substrate targeting.
abstract: Snake venom metalloproteinases (SVMPs) are members of the Reprolysin family of metalloproteinases to which the ADAM (a disintegrin and metalloproteinase) proteins also belong. The disintegrin-like/cysteine-rich domains of the ADAMs have been implicated in their function. In the case of the SVMPs, we hypothesized that these domains could function to target the metalloproteinases to key extracellular matrix proteins or cell surface proteins. Initially we detected interaction of collagen XIV, a fibril-associated collagen with interrupted triple helices containing von Willebrand factor A (VWA) domains, with the PIII SVMP catrocollastatin. Next we investigated whether other VWA domain-containing matrix proteins could support the binding of PIII SVMPs. Using surface plasmon resonance, the PIII SVMP jararhagin and a recombinant cysteine-rich domain from a PIII SVMP were demonstrated to bind to collagen XIV, collagen XII, and matrilins 1, 3, and 4. Jararhagin was shown to cleave these proteins predominantly at sites localized at or near the VWA domains suggesting that it is the VWA domains to which the PIII SVMPs are binding via their cysteine-rich domain. In light of the fact that these extracellular matrix proteins function to stabilize matrix, targeting the SVMPs to these proteins followed by their specific cleavage could promote the destabilization of extracellular matrix and cell-matrix interactions and in the case of capillaries could contribute to their disruption and hemorrhage. Although there is only limited structural homology shared by the cysteine-rich domains of the PIII SVMPs and the ADAMs our results suggest an analogous function for the cysteine-rich domains in certain members of the expanded ADAM family of proteins to target them to VWA domain-containing proteins.
authors.affiliation: Laboratório Especial de Toxinologia Aplicada/Center for Applied Toxinology, Instituto Butantan, 05503-900 Sao Paulo, Brazil.
authors.forename: Solange M T
authors.initials: SM
authors.lastname: Serrano
authors.forename: Junho
authors.initials: J
authors.lastname: Kim
authors.forename: Deyu
authors.initials: D
authors.lastname: Wang
authors.forename: Bojan
authors.initials: B
authors.lastname: Dragulev
authors.forename: John D
authors.initials: JD
authors.lastname: Shannon
authors.forename: Henning H
authors.initials: HH
authors.lastname: Mann
authors.forename: Guido
authors.initials: G
authors.lastname: Veit
authors.forename: Raimund
authors.initials: R
authors.lastname: Wagener
authors.forename: Manuel
authors.initials: M
authors.lastname: Koch
authors.forename: Jay W
authors.initials: JW
authors.lastname: Fox
mesh_terms: D000818:Animals; D017837:Bothrops; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D003435:Crotalid Venoms / Q000737:chemistry / Q000378:metabolism*; D017839:Crotalus; D003545:Cysteine / Q000378:metabolism* / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D064235:Matrilin Proteins; D008666:Metalloendopeptidases / Q000378:metabolism; D045726:Metalloproteases / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000502:physiology; D013379:Substrate Specificity; D014841:von Willebrand Factor / Q000737:chemistry / Q000378:metabolism*; D000097146:Bothrops jararaca Venom
chemical_list: D003094:Collagen; D003435:Crotalid Venoms; D003545:Cysteine; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D008024:Ligands; D064235:Matrilin Proteins; D008666:Metalloendopeptidases; D045726:Metalloproteases; D014841:von Willebrand Factor; D000097146:Bothrops jararaca Venom; C054447:COL14A1 protein, human; C093237:catrocollastatin