ADAM and ADAMTS Family Proteins and Snake Venom Metalloproteinases: A Structural Overview

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.

Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy

“…The ADAMs are type‐1 transmembrane proteins with distinct modular domains that include an N‐terminus metalloproteinase domain, disintegrin‐like domain, cysteine‐rich domain, an epidermal growth factor domain, which ADAM17 happens to lack, and transmembrane and cytoplasmic regions . More than 20 ADAMs have been identified in humans, although 12 are proteolytically active . ADAM17 is constitutively expressed on the surface of NK cells, and it cleaves its substrates typically in a cis manner at an extracellular location proximal to the cell membrane .…”

“…ADAM17 is a member of the adamalysin subfamily of the metzincin metalloproteinase superfamily, which contain a conserved methionine amino acid adjacent to a zinc-binding motif in the catalytic region of the proteases. 33,34 The ADAMs are type-1 transmembrane proteins with distinct modular domains that include an N-terminus metalloproteinase domain, disintegrin-like domain, cysteine-rich domain, an epidermal growth factor domain, which ADAM17 happens to lack, and transmembrane and cytoplasmic regions. 35 More than 20…”

Ectodomain Shedding by ADAM17: Its Role in Neutrophil Recruitment and the Impairment of This Process during Sepsis

“…These domains contain cysteine residues that provide strictly conserved disulfide bonds (Takeda, 2016). ADAM17 has two highly conserved cysteine-X-X-cysteine sequences (CXXC, where XX represents two other amino acids), one located in the disintegrin-like domain and the other in the cysteine-rich domain (Figure 2) (Wang et al, 2009).…”

Procyanidin B3 alleviates intervertebral disc degeneration via interaction with the TLR4/MD‐2 complex

“…40 MMP-13 is a collagenase with the high specificity for collagen II breakdown and ADAMTS-5 expedites cytokine-triggered aggrecan degradation. 41 This study display that Pro-B3 can significantly inhibit overproduction of NO, PGE2, iNOS, and COX-2 proteins in NP cells treated with LPS. The same effects were observed for TNF-α and IL-6.…”