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J. Biol. Chem., Vol. 283, Issue 6, 3224-3230, February 8, 2008

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Platelet Fragmentation Requires a Specific Structural Conformation of Human Monoclonal Antibody against β3 Integrin^*

Zongdong Li¹, Michael A. Nardi, Jing Wu, Ruimin Pan, Wei Zhang, and Simon Karpatkin²

From the Departments of Medicine and Pediatrics, New York University School of Medicine, New York, New York 10016

We have described an autoantibody against β3 (GPIIIa49–66), a region of platelet integrin IIbβ3 that is unique. It induces platelet fragmentation in the absence of complement via antibody activation of platelet NADPH oxidase and 12-lipoxygenase to release reactive oxygen species, which destroy platelets. To study the mechanism of anti-GPIIIa antibody-induced platelet fragmentation, we screened a human single chain Fv antibody library with the GPIIIa49–66 peptide. Nine monoclonal antibodies were identified that were capable of binding to GPIIIa49–66. Surprisingly, binding avidity for GPIIIa49–66 did not correlate with activity of induction of platelet fragmentation. We therefore investigated the requirements for platelet fragmentation. Mutations were introduced into the heavy chain complementary-determining region-3 of clones 11, 43, and 54 by site-directed mutagenesis. The capability of these clones to induce platelet fragmentation or bind to GPIIIa49–66 subsequently changed. Molecular modeling of these clones with their mutants revealed that the ability to induce platelet fragmentation is affected by the side chain orientation of positively charged amino acids in the heavy chain of residues 99–102. Thus, a structural change in the conformation of anti-GPIIIa49–66 antibody contributes to its binding to the β3 integrin and subsequent antibody-induced platelet fragmentation and aggregate dissolution.

Received for publication, July 18, 2007 , and in revised form, November 27, 2007.

^* This work was supported by National Institutes of Health Grants K01 DA020816, HL13336, and DAO-04315, the Dorothy and Seymour Weinstein Platelet Research Fund, and New York University Center for AIDS Research Grant 30-1-7649. 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 To whom correspondence may be addressed. E-mail: liz04{at}med.nyu.edu. ² To whom correspondence may be addressed: Dept. of Medicine, New York University School of Medicine, TH451, 550 1st Ave., New York, NY 10016. Tel.: 212-263-5609; Fax: 212-263-0695; E-mail: simon.karpatkin{at}med.nyu.edu.

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