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J. Biol. Chem., Vol. 279, Issue 39, 40252-40254, September 24, 2004

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A Novel Adaptation of the Integrin PSI Domain Revealed from Its Crystal Structure^*

Jian-Ping Xiong, Thilo Stehle, Simon L. Goodman¶, and M. Amin Arnaout||

From the Structural Biology Program, Leukocyte Biology and Inflammation Program, Renal Unit, the Laboratory of Developmental Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129 and ^¶Oncology Research, Merck KGaA, Darmstadt 64271, Germany

Integrin -subunits contain an N-terminal PSI (for plexin-semaphorin-integrin) domain that contributes to integrin activation and harbors the PI(A) alloantigen associated with immune thrombocytopenias and susceptibility to sudden cardiac death. Here we report the crystal structure of PSI in the context of the crystallized _V3 ectodomain. The integrin PSI forms a two-stranded antiparallel -sheet flanked by two short helices; its long interstrand loop houses Pl(A) and may face the EGF2 domain. The integrin PSI contains four cysteine pairs connected in a 1-4, 2-8, 3-6, 5-7 pattern. An unexpected feature of the structure is that the final, eighth cysteine is located C-terminal to the Ig-like hybrid domain and is thus separated by the hybrid domain from the other seven cysteines of PSI. This architecture may be relevant to the evolution of integrins and should help refine the current models of integrin activation.

Received for publication, August 2, 2004 , and in revised form, August 6, 2004.

^* This work was supported by National Institutes of Health Grants HL70219 and DK48549. 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.

The atomic coordinates and structure factors (code 1U8C) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^|| To whom correspondence should be addressed: Renal Unit, Massachusetts General Hospital, 149 13th St., Charlestown, MA 02129. Tel.: 617-726-5663; Fax: 617-726-5671; E-mail: arnaout{at}receptor.mgh.harvard.edu.

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