Divalent cations and the relationship between alphaA and betaA domains in integrins.
Integrins contain either one or two von Willebrand factor A-like domains, which are primary ligand and cation binding regions in the molecules. Here we examine the first structure of an A domain of a beta subunit, in alphanubeta3 and compare it to known A domain structures of alpha subunits. Ligand binding to immobilized alphanubeta3 domain is stimulated by Ca2+ rather than inhibited by it. Biochemical, cell biological and structural evidence suggests that the A domain is a major site of ligand interaction in alphanubeta3. The Arg-Gly-Asp based inhibitor cilengitide (EMD 121974) inhibites ligand interaction with transmembrane-truncated alphanubeta3 in the presence of either Ca2+ or Mn2+ ions, and does so with similar kinetics. The alphanubeta3 structure reveals that both the alphaA and betaA domains share common structural cores. But, in contrast to alphaA, the betaA domain has three cation binding sites, that are involved either directly or indirectly in ligand binding. Structural alignment of alphaA and betaA domains reveals additional loops unique only to the betaA domain and much evidence support that that these loops are important for ligand binding specificity and for the interaction between alpha and beta subunits. Since the position of these loops are evolutionary conserved but their primary sequence varies between the various betaA domains, they represents potential targets for dissecting functional diversity among integrins.
Seow
Kah-Tong
KT
Department of Bio- and Chemoinformatics, Merck KGaA, Frankfurterstr. 250, Darmstadt, Germany.
Xiong
Jian-Ping
JP
Arnaout
M Amin
MA
Welge
Jutta
J
Rippmann
Friedrich
F
Goodman
Simon L
SL
D001665:Binding Sites; D002412:Cations / Q000737:chemistry*; D003460:Crystallization; D006801:Humans; D016023:Integrins / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D019030:Receptors, Vitronectin / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry
D002412:Cations; D016023:Integrins; D008024:Ligands; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins