Transcript ADAM
ADAM introduction Nan Song 2004/3/20 ADAM • Contain: A Disintegrin And Metalloprotease Domain • Other names: – Cellular disintegrins – MDCs (metalloprotease/ disintegrin/cysteine) ADAM • A large family of membrane anchored cell surface proteins • All ADAMs described to date have the same domain organization The protease domain Pro Metalloprotease-like Disintegrin-like Cysteine-rich EGF Cytoplasmic domains • Part of a superfamily of zinc-dependent metalloproteases. • All metazincins contains 5-stranded beta sheets 3 alpha helices a active site sequence: HEXXHXXGXXH • Other metzincins do not share any additional domains with SVMPs or ADAMs metzicins include astacins, matrixins, svmp, and serralysins • Most metzincins are soluble proteins. The adhesion domain Pro Metalloprotease-like Disintegrin-like Cysteine-rich EGF Cytoplasmic domains Function of disintegrin domain Some popular membrane bound adhesion domains Schematic representation of integrins. Both integrin alpha and beta subunits have a single large extracellular domain, one transmembrane region, and a short cytoplasmic tail without known enzymatic activity. Integrins bind to a variety of extracellular ligands including other transmembrane proteins such ADAM and IgG-domain proteins in addition to the extracellular matrix (ECM). The binding of ligands can modulate a number of intracellular processes including activation of focal adhesion kinase (FAK) and reorganization of the actin cytoskeleton. Intriguingly, integrins also mediate inside-out signaling whereby cytoplasmic molecules such as protein kinase C (PCK) can modify the affinity of integrins for their ligands. www.msu.edu/~grotewie/ lab/Research.htm Introduction of Disintegrin-like Pro Metalloprotease-like Disintegrin-like Cysteine-rich EGF Cytoplasmic domains • Disintegrin (canonical): contain a 13 amino acid loop which protrudes from the core structure and continas, at its tip, the sequence RGD • Disintegrin-like: the active binding loop is a great deal more degenerate among the ADAM …. this may be related to ADAM function, such as… Potential cell-fusion domain Pro Metalloprotease-like Disintegrin-like Cysteine-rich EGF Cytoplasmic domains • potential fusion peptide: a relatively hydrophobic stretch of ~23 amino acids embedded in the cysteine-rich domain • The presence or absence of these characteristics is conserved among the orthologs of a given ADAM. For example, all ADAM1s sequence contains, whereas the ADAM2s do not. Potential signaling domain Pro Metalloprotease-like Disintegrin-like Cysteine-rich EGF Cytoplasmic domains • potential signaling domain (Cytoplasmic domains) • range in length from 11-176 amino acids • do not share significant sequence similarity with each other or with other proteins ADAM function • Four potential functions of the ADAMs: – – – – Proteolysis Cell adhesion Cell fusion Signaling • All are not capable of manifesting all the potential functions of proteolysis, adhesion, fusion and signaling • ASAMs are zinc dependent metalloproteinase with high amino acid sequence homology and domain organization similar to SVMP (snake venom metalloproteinase) Domain architecture comparison of ADAM and other proteins • ADAM have been implicated in many processes such as proteolysis of extracellular matrix and extracellular communication and/or intracellular signaling. In addition, they are also involved in events such as the processing of plasma membrance proteins, proteolysis in the secretory pathway and procytokine conversion From: http://ntri.tamuk.edu/homepage-ntri/lectures/protein/regulate.gif http://www.medicine.ox.ac.uk/ndog/mardon/images/integrin.jpg