1. ADAM introduction Nan Song 2004/3/20

2. ADAM Contain: A Disintegrin And Metalloprotease Domain Other names: –Cellular disintegrins –MDCs (metalloprotease/ disintegrin/cysteine)

3. ADAM A large family of membrane anchored cell surface proteins All ADAMs described to date have the same domain organization

4. 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.

5. The adhesion domain Pro Metalloprotease-like Disintegrin-like Cysteine-rich EGF Cytoplasmic domains

6. Function of disintegrin domain

7. Some popular membrane bound adhesion domains

8. 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

9. 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…

10. 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.

11. 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

12. 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

13. ASAMs are zinc dependent metalloproteinase with high amino acid sequence homology and domain organization similar to SVMP (snake venom metalloproteinase)

14. Domain architecture comparison of ADAM and other proteins

15. 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

17. From: http://ntri.tamuk.edu/homepage-ntri/lectures/protein/regulate.gif

18. http://www.medicine.ox.ac.uk/ndog/mardon/images/integrin.jpg