A prototypical ADAM. The pro domain (yellow) is postulated to regulate the activity of a metalloprotease domain (red), maintaining the latency of the protease. The metalloprotease has been characterized best for its ability to execute the critical function of ectodomain shedding (refer to next figure). ADAM disintegrin domains (green) have been clearly demonstrated to interact with multiple integrin superfamily of adhesion receptors. Cysteine-rich domains interact with syndecans and studies suggest that this domain and the disintegrin domain interact. The role of the EGF domain has not been resolved. Some members of the ADAM family have splice variants that lack a transmembrane domain allowing them to be completely soluble. The cytoplasmic tail of the ADAMs have been shown to interact with multiple cytoplasmic structural and signaling proteins.
Role of ADAMs as sheddases. An ADAM metalloprotease represented as a “pac-man”, recognizes a membrane-bound substrate (red, S). CLeavage or processing of the membrane-bound substrate generates a soluble ligand (red, L) that can diffuse from the cell and reach its receptor (blue, R) in another location.
Functional models of integrin mediated shedding. ADAM molecules are shown as linear domain organizations. Integrin receptor is depicted as a ball-and-stick model. A generic ADAM proteolytic substrate expressed at the cell surface is represented in yellow with the ADAM cleavage site denoted in red. A) ADAM-integrin association facilitate the localization of the ADAM to its proteolytic substrate promoting shedding. B) ADAM-integrin recognition serves to sequester the protease and prevent cleavage. Upon dissociation of the ADAM-integrin complex the ADAM diffuses freely and encounters and subsequently processes the substrate.
Figures Adapted with permission from:
Bridges, LC and RD Bowditch. 2005. ADAM-Integrin Interactions: potential integrin regulated ecotdomain shedding activity. Curr Pharm Des 11:837
White JM, LC Bridges, DW DeSimone, M Tomczuk, and TG Wolfsberg. 2005. Introduction to the ADAMs Family. Proteases in Biology and Disease. NM Hooper and U Lendeckel, Editors. Springer. vol 4 pgs1-28.
My research interests entail characterizing the biochemical properties and defining the biological roles of a unique family of proteins known as the ADAMs (a disintegrin and metalloprotease). ADAMs were initially identified for their role in fertilization by Dr. Judith White (White Lab home) and are named for their most defining features: a disintegrin and metalloprotease domain. Disintegrins are snake venom constituents that are potent anticoagulants. By serving as platelet integrin receptor antagonists, snakes venom disintegrins increase the efficacy of venom by allowing broader diffusion throughout a bite victim. Mammalian disintegrins contained within the ADAM family represent a novel class of integrin ligand. However their biological role while certainly distinct from their snake venom relatives remains poorly defined. The other salient feature of the ADAMs, a metalloprotease, is well-characterized and has established roles in a process known as ectodomain shedding. My lab seeks to shed light on how these domains may act in concert to govern when and where a particular ADAM sheddase substrate is released. Current models posit that protease specificity is bestowed upon an ADAM indirectly by its disintegrin ligand properties. We are currently interested in ADAMs predominately expressed by immune cells and how these particular members may regulate inflammation.
