title: Identification of sites in the cysteine-rich domain of the class P-III snake venom metalloproteinases responsible for inhibition of platelet function.
abstract: Atrolysin A and jararhagin are class P-III snake venom metalloproteinases (SVMPs) with three distinct domains: a metalloproteinase, a disintegrin-like and a cysteine-rich. The metalloproteinase and the disintegrin-like domains of atrolysin A and jararhagin contain peptide sequences that interact with alpha2beta1 integrin and inhibit the platelet responses to collagen. Recently, the recombinant cysteine-rich domain of atrolysin A was shown to have similar effects, but the sequence(s) responsible for this is unknown. In this report, we demonstrate two complete peptide sequences from the homologous cysteine-rich domains of atrolysin A and jararhagin that inhibit both platelet aggregation by collagen and adhesion of alpha2-expressing K562 cells to this protein. In addition, the peptide effects on platelets do not seem to involve an inhibition of GPVI. These results identify, for the first time, sites in the cysteine-rich domain of SVMPs that inhibit cell responses to collagen and reveal the complexity of the potential biological effects of these enzymes with multifunctional domains.
authors.affiliation: Department of Haematology, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK. aurakami@liverpool.ac.uk
authors.forename: Aura S
authors.initials: AS
authors.lastname: Kamiguti
authors.forename: Paul
authors.initials: P
authors.lastname: Gallagher
authors.forename: Cezary
authors.initials: C
authors.lastname: Marcinkiewicz
authors.forename: R David G
authors.initials: RD
authors.lastname: Theakston
authors.forename: Mirko
authors.initials: M
authors.lastname: Zuzel
authors.forename: Jay W
authors.initials: JW
authors.lastname: Fox
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D003094:Collagen / Q000187:drug effects; D003435:Crotalid Venoms / Q000737:chemistry / Q000494:pharmacology; D003545:Cysteine; D006801:Humans; D039421:Integrin alpha2 / Q000378:metabolism; D020014:K562 Cells; D008666:Metalloendopeptidases / Q000737:chemistry* / Q000494:pharmacology*; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D012910:Snake Venoms / Q000201:enzymology*; D000097146:Bothrops jararaca Venom
chemical_list: D003094:Collagen; D003435:Crotalid Venoms; D003545:Cysteine; D039421:Integrin alpha2; D008666:Metalloendopeptidases; D010975:Platelet Aggregation Inhibitors; D012910:Snake Venoms; D000097146:Bothrops jararaca Venom; C044577:atrolysin A