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Role of the β-Subunit Arginine/Lysine Finger in Integrin Heterodimer Formation and Function¹

Division of Nephrology, Leukocyte Biology and Inflammation Program, Structural Biology Program, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129

Formation of the integrin β heterodimer is essential for cell surface expression and function. At the core of the β interface is a conserved Arg/Lys "finger" from the β-subunit that inserts into a cup-like "cage" formed of two layers of aromatic residues in the -subunit. We evaluated the role of this residue in heterodimer formation in an A-lacking and an A-containing integrin Vβ3 and Mβ2 (CD11b/CD18), respectively. Arg261 of β3 was mutated to Ala or Glu; the corresponding Lys252 of β2 was mutated to Ala, Arg, Glu, Asp, or Phe; and the effects on heterodimer formation in each integrin examined by ELISA and immunoprecipitation in HEK 293 cells cotransfected with plasmids encoding the - and β-subunits. The Arg261Glu (but not Arg261Ala) substitution significantly impaired cell surface expression and heterodimer formation of Vβ3. Although Lys252Arg, and to a lesser extent Lys252Ala, were well tolerated, each of the remaining substitutions markedly reduced cell surface expression and heterodimer formation of CD11b/CD18. Lys252Arg and Lys252Ala integrin heterodimers displayed a significant increase in binding to the physiologic ligand iC3b. These data demonstrate an important role of the Arg/Lys finger in formation of a stable integrin heterodimer, and suggest that subtle changes at this residue affect the activation state of the integrin.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Grants DK48549, DK50305, and DK068253 from the National Institutes of Health.

² V.G. and J.L.A. are joint first authors.

³ Address correspondence and reprint requests to Dr. M. Amin Arnaout, Nephrology Division, Massachusetts General Hospital, 149 13th Street, Charlestown, MA, 02129. E-mail address: arnaout{at}receptor.mgh.harvard.edu

⁴ Abbreviations used in this paper: VWFA, von Willebrand factor type A; MIDAS, metal-ion-dependent adhesion site; WT, wild type.

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