Abstract
The ADAM (a disintegrin-like and metalloproteinase) proteins are a family of transmembrane cell-surface proteins with important functions in adhesion and proteolytic processing in all animals. Human ADAM-15 is the only member of the ADAM family with the integrin binding motif Arg-Gly-Asp (RGD) in its disintegrin-like domain. This motif is also found in most snake venom disintegrins and other disintegrin-like proteins. This unique RGD motif within ADAM-15 serves as an integrin ligand binding site, through which it plays a pivotal role in interacting with integrin receptors, a large family of heterodimeric transmembrane glycoproteins. This manuscript will present a review of the RGD-containing disintegrin-like domain structures and the structural features responsible for their activity as antagonists of integrin function in relation to the canonical RGD template.
Highlights
The “disintegrin” terminology was initially applied in 1990 to describe a family of cysteine-rich, RGD-containing proteins, isolated from the venom of snakes that inhibit platelet aggregation and integrin-mediated cell adhesion [1,2,3]
We have shown that ddADAM-15 can bind to airway smooth muscle cells (ASMCs) and this binding can be modulated by putative disintegrin-like loops within the ddADAM-15 scaffold [80]
The amino acid sequence in the putative disintegrin-like loop plays a crucial role in controlling the selectivity and specificity of the ADAM proteins in their interaction with particular integrins
Summary
The “disintegrin” terminology was initially applied in 1990 to describe a family of cysteine-rich, RGD-containing proteins, isolated from the venom of snakes that inhibit platelet aggregation and integrin-mediated cell adhesion [1,2,3]. The term “disintegrins” was eventually reserved for a particular form of snake venom toxins, and the term “disintegrin-like protein” for RGD proteins with similar properties but different general structures, including the disintegrin-like/cysteine-rich (D/C) domains of the PIII class snake venom metalloproteinases (SVMP) [13,14]; the ADAM (a disintegrin-like and metalloproteinase) [15,16,17,18] and ADAMTS (ADAM with thrombospondin motifs) [19,20]; ADAMTSL (ADAMTS-like) families [21]. The primary sequences of disintegrin-like domains in the ADAMs family were homologous to those found in snake venom disintegrins. These proteins constitute one subfamily of the so-called adamalysins, which is a protein family belonging to metzincin superfamily of metalloproteinases. We focus on the disintegrin-like domain in ADAM 15 and its structure and function
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