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Science 2 May 2003:
Vol. 300. no. 5620, pp. 795 - 798
DOI: 10.1126/science.1079441
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Reports

Activation of Integrin {alpha}IIbß3 by Modulation of Transmembrane Helix Associations

Renhao Li,1 Neal Mitra,2 Holly Gratkowski,1 Gaston Vilaire,2 Rustem Litvinov,3 Chandrasekaran Nagasami,3 John W. Weisel,3 James D. Lear,1 William F. DeGrado,1* Joel S. Bennett2*

Transmembrane helices of integrin {alpha} and ß subunits have been implicated in the regulation of integrin activity. Two mutations, glycine-708 to asparagine-708 (G708N)and methionine-701 to asparagine-701, in the transmembrane helix of the ß3 subunit enabled integrin {alpha}IIbß3 to constitutively bind soluble fibrinogen. Further characterization of the G708N mutant revealed that it induced {alpha}IIbß3 clustering and constitutive phosphorylation of focal adhesion kinase. This mutation also enhanced the tendency of the transmembrane helix to form homotrimers. These results suggest that homomeric associations involving transmembrane domains provide a driving force for integrin activation. They also suggest a structural basis for the coincidence of integrin activation and clustering.

1 Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2 Hematology-Oncology Division, Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3 Department of Cell and Developmental Biology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

* To whom correspondence should be addressed. E-mail: wdegrado{at}mail.med.upenn.edu (W.F.D.); bennetts{at}mail.med.upenn.edu (J.S.B.)

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