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 additionaldomains 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