16 nots - 1 Lecture # 16 November 5, 2008 ADAMs, ADAMTSs...

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1 Lecture # 16 November 5, 2008 ADAMs, ADAMTSs and Laminin and epithelial morphogenesis (embryoid body formation) References Manso et al (2006) Integrins, membrane-type metalloproteinases and ADAMS: potential implications for cardiac remodeling. Cardiovascular research 69: 574-584 and Primakoff and Myles (2000) The ADAM gene family: surface proteins with adhesion and protease activity Trends in Genetic 16: 83-87 The structures of ADAMs consist of a prodomain, a metalloproteinase domain, a disintegrin domain, a metalloproteinase domain, a disintegrin domain , a cysteine-rich domain, a transmembrane domain, and a cytoplasmic tail. The N-terminal prodomain functions principally to keep the metalloproteinase site inactive, but also acts as a chaperone for proper folding of ADAMSs’ metalloproteinase domain. The metalloproteinase domain hydrolyzes protein substrates such as cytokines and growth factors. The disintegrin domain binds matrix ligands of integrin receptors such as fibronectin. Eleven ADAM disintegrin domains are known to interact with integrin receptors at the specific location of the “disintegrin loop” found on many ADAM molecules. ADAMS cleavage schematic shown in class The ADAMs (white) uses its disintegrin domain to bind to the substrate (dark grey) and uses it zinc-containing metalloproteinase active site to cleave the substrate. After cleavage, the substrate undergoes conformation change, dissociates from the disintegrin domain and the substrate’s large extracellular fragment is released from the cell surface. Another version of the model, the ADAM (white) uses its disintegrin domain to bind to a substrate-associated protein (light grey) and uses its zinc-containing metalloproteinase active site to cleave the substrate (dark grey). Following cleavage, the substrate undergoes conformational change, dissociates from the substrate-associated-protein and the substrate’s large extracellular fragment is released from the cell surface. Some ADAM proteases are sheddases During development and in the adult, cells have the ability to modify their surface to regulate various kinds of functions. For example, the extracellular domain of >40 plasma membrane-anchored cytokines, growth factors, receptors, adhesion molecules and enzymes can be cleaved and thereby released (shed) from the plasma membrane by various proteases (called sheddases or secretases). These sheddases are themselves transmembrane proteins and, in several cases, are ADAMs and MT-MMPs. The role of ADAM-12 in the hypertrophic process GPCR (G-protein coupled receptors) stimulation by agonists such as PE, AII or ET-1 (see slide) leads to ADAM-12 activation. The activated ADAM evokes ectodomain shedding
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2 of the heparin-binding epidermal growth factor (HB-EGF) to allow EGF stimulation of the cognate receptor. In turn this activates MAPK signaling and cardiac hypertrophy. The main message is that the protease activity of MMPs, ADAMs must be regulated to
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This note was uploaded on 09/29/2009 for the course CSB csb327 taught by Professor Ringuitte during the Fall '08 term at University of Toronto- Toronto.

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16 nots - 1 Lecture # 16 November 5, 2008 ADAMs, ADAMTSs...

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