Two Functional States of the CD11b A-Domain: Correlations with Key Features of Two Mn2+-complexed Crystal Structures

doi:10.1083/jcb.143.6.1523

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© The Rockefeller University Press, 0021-9525/1998//1523 $5.00
The Journal of Cell Biology, Volume 143, Number 6, , 1998 1523-1534

Article

Two Functional States of the CD11b A-Domain: Correlations with Key Features of Two Mn²⁺-complexed Crystal Structures

Rui Li, Philippe Rieu, Diana L. Griffith, David Scott, and M. Amin Arnaout

Leukocyte Biology and Inflammation Program, Renal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129

In the presence of bound Mn²⁺, the three- dimensional structureof the ligand-binding A-domain from the integrin CR3 (CD11b/CD18)is shown to exist in the "open" conformation previously describedonly for a crystalline Mg²⁺ complex. The open conformation is distinguished from the "closed" form by the solvent exposureof F302, a direct T209–Mn²⁺ bond, and the presence ofa glutamate side chain in the MIDAS site. Approximately 10%of wild-type CD11b A-domain is present in an "active" state(binds to activation-dependent ligands, e.g., iC3b and the mAb7E3). In the isolated domain and in the holoreceptor, the percentageof the active form can be quantitatively increased or abolishedin F302W and T209A mutants, respectively. The iC3b-bindingsite is located on the MIDAS face and includes conformationallysensitive residues that undergo significant shifts in the openversus closed structures. We suggest that stabilization ofthe open structure is independent of the nature of the metalligand and that the open conformation may represent the physiologicallyactive form.

Key Words: integrin activation • A-domain • crystal structure • complement iC3b • G proteins

Abbreviations used in this paper: MFI, mean fluorescence intensity; MIDAS, metal ion–dependent adhesion site; NIF, neutrophil inhibitory factor; WT, wild-type.

Grants from the National Institutes of Health and a fellowshipgrant from the American Heart Association and the PhilippeFoundation supported this work. The Brookhaven National LightSource Facility is supported by the US Department of Energy,Office of Health and Environmental Research, and by the NationalScience Foundation.

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