Abstract
A disintegrin and metalloproteinase (ADAM) family proteins constitute a major class of membrane-anchored multidomain proteinases that are responsible for the shedding of cell-surface protein ectodomains, including the latent forms of growth factors, cytokines, receptors and other molecules. Snake venom metalloproteinases (SVMPs) are major components in most viper venoms. SVMPs are primarily responsible for hemorrhagic activity and may also interfere with the hemostatic system in envenomed animals. SVMPs are phylogenetically most closely related to ADAMs and, together with ADAMs and related ADAM with thrombospondin motifs (ADAMTS) family proteinases, constitute adamalysins/reprolysins or the M12B clan (MEROPS database) of metalloproteinases. Although the catalytic domain structure is topologically similar to that of other metalloproteinases such as matrix metalloproteinases, the M12B proteinases have a modular structure with multiple non-catalytic ancillary domains that are not found in other proteinases. Notably, crystallographic studies revealed that, in addition to the conserved metalloproteinase domain, M12B members share a hallmark cysteine-rich domain designated as the “ADAM_CR” domain. Despite their name, ADAMTSs lack disintegrin-like structures and instead comprise two ADAM_CR domains. This review highlights the current state of our knowledge on the three-dimensional structures of M12B proteinases, focusing on their unique domains that may collaboratively participate in directing these proteinases to specific substrates.
Highlights
A disintegrin and metalloproteinase (ADAM) family proteins, known as metalloproteinase-disintegrins or metalloproteinase/disintegrin-like/cysteine-rich (MDC) proteins, are type-I transmembrane and soluble glycoproteins that have diverse functions in cell adhesion, migration, proteolysis and signaling [1,2,3]
ADAMs, ADAM with thrombospondin motifs (ADAMTS) and Snake venom metalloproteinases (SVMPs) share a topological similarity with matrix metalloproteinases (MMPs) in the structure of their catalytic domain [40]
Theclosed closed conformation conformation isisdepicted in cyan, the open conformation is shown in pink.in configurations: depicted in cyan, the open conformation is shown (E) Amino acid sequence alignments of ADAMTSs around thearound
Summary
A disintegrin and metalloproteinase (ADAM) family proteins, known as metalloproteinase-disintegrins or metalloproteinase/disintegrin-like/cysteine-rich (MDC) proteins, are type-I transmembrane and soluble glycoproteins that have diverse functions in cell adhesion, migration, proteolysis and signaling [1,2,3]. ADAMTS members contain a varying number of C-terminal thrombospondin type-1 motifs in place of the ADAM transmembrane and cytoplasmic domains and function as secreted proteinases [14,15]. Different ADAMTS recognize very distinct substrates but the non-catalytic domains that characterize each ADAMTS family member may perform similar functions in other ADAMTS. ADAMs, ADAMTSs and SVMPs share a topological similarity with matrix metalloproteinases (MMPs) in the structure of their catalytic domain [40]. P-III SVMPs can be divided further into subclasses depending on their post-translational modifications, such as proteolytic processing between the M and D domains (P-IIIb) or dimerization (P-IIIc), complexation (P-IIId) with additional snake venom C-type lectin-like proteins (snaclecs) [57], in addition to the canonical P-IIIa SVMPs. SVMPs of different classes are often present in the same viper venom. 41 residues) and is not required for its secretion and function [63]
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