The """"""""A"""""""" domain, or """"""""I"""""""" domain as it is commonly called in integrins, is a approximately 200 residue protein recognition module that is present in many proteins involved in cell-cell and cell-matrix adhesion. In most cases tested, key ligand binding properties of the parent molecule are recapitulated by recombinant A domains, demonstrating that this domain is a critical element in the adhesion function. This in turn suggests that the A domain is an attractive target for therapeutic agents that would disrupt aberrant adhesion. We have previously determined the crystal structures of four members of this family and proposed a general model for ligand recognition involving the upper surface of the domain. In the integrins, a metal ion is located at the putative ligand binding interface, which we have called the """"""""metal ion-dependent adhesion site"""""""" or MIDAS motif. In addition, we have proposed that the adhesiveness of A domains is dependent on tertiary structure changes within the A domain (""""""""shape-shifting"""""""") that create a high affinity ligand binding surface, in which the domain switches from a """"""""closed"""""""" to an """"""""open conformation. We now wish to test and extend these hypotheses by determining crystal structures of A domains in complex with their ligands. Specifically, we will target complexes of the integrin alpha1 and alpha2 I domains and the von Willebrand Factor A3 domain with triple helical collagen-like peptides; the integrin alphaM I domain with fragments of fibrinogen and ICAM-1; the integrin alpha2 I domain with a fragment of laminin; and the von Willebrand Factor A1 domain with a fragment of glycoprotein lb and the snake toxin botrocetin. Successful structure determination of a range of these targets will enable us to address the following questions: What are the common and distinct features of ligand recognition by the A/I domain family? Is a metal bridge a general feature of integrin-ligand contacts? What replaces the metal in the vWF A domains? Is tertiary """"""""shape- shifting"""""""" a common feature of A/I domains, and does this represent a mechanism for regulation? And finally, do our structural data suggest strategies for the design of small molecules that would mimic ligand binding and disrupt adhesion?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061771-03
Application #
6520312
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Flicker, Paula F
Project Start
2000-06-01
Project End
2004-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
3
Fiscal Year
2002
Total Cost
$292,500
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
009214214
City
La Jolla
State
CA
Country
United States
Zip Code
92037