Structure-Function Relationship of Modular Domains of P-III Class Snake Venom Metalloproteinases

Abstract

Snake venom metalloproteinases (SVMPs) are among the most abundant toxins in many venoms of the Viperidae. SVMPs are primarily responsible for the hemorrhagic activity of venoms and may also interfere with the hemostatic system. Phylogenetically, SVMPs are most closely related to the mammalian ADAM (a disintegrin and metalloproteinase) protein family, a major class of membrane-bound sheddases. Together with ADAMs and the related ADAMTS (ADAM with thrombospondin type-1 motif) family of proteins, SVMPs constitute the M12B clan of zinc metalloproteinases. SVMPs are zinc-dependent proteinase ranging in size from 20 to 110 kDa, and they are categorized into classes P-I, P-II, and P-III according to their domain organization. Although all SVMPs share a catalytic metalloproteinase (M)-domain structure that is topologically similar to those of matrix metalloproteinases (MMPs), large P-III SVMPs have a modular structure with multiple non-catalytic ancillary domains that are not found in MMPs. P-III SVMPs generally have higher hemorrhagic activity and more diverse functions than P-I SVMPs, which only contain the metalloproteinase domain, suggesting that the non-catalytic domains are functionally important. Recent crystallographic studies of various subclasses of P-III SVMPs and mammalian ADAM/ ADAMTS proteins have shed new light on the structure-function relationships of these modular proteinases. This chapter will focus on the three-dimensional structures of P-III SVMPs, particularly their non-catalytic domains, which may participate in directing these proteinases to specific substrates.