A push-pull mechanism for regulating integrin function

Wei Li, Douglas G. Metcalf, Roman Gorelik, Renhao Li, Neal Mitra, Vikas Nanda, Peter B. Law, James D. Lear, William F. DeGrado, Joel S. Bennett

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

Homomeric and heteromeric interactions between the αIIb and β3 transmembrane domains are involved in the regulation of integrin αIIbβ3 function. These domains appear to interact in the inactivated state but separate upon integrin activation. Moreover, homomeric interactions may increase the level of αIIbβ3 activity by competing for the heteromeric interaction that specifies the resting state. To test this model, a series of mutants were examined that had been shown previously to either enhance or disrupt the homomeric association of the allb transmembrane domain. One mutation that enhanced the dimerization of the allb transmembrane domain indeed induced constitutive αIIbβ3 activation. However, a series of mutations that disrupted homodimerization also led to αIIbβ3 activation. These results suggest that the homo- and heterodimerization motifs overlap in the αIIb transmembrane domain, and that mutations that disrupt the αIIb/β3 transmembrane domain heterodimer are sufficient to activate the integrin. The data also imply a mechanism for αIIbβ3 regulation in which the integrin can be shifted from its inactive to its active state by destabilizing an αIIb/β3 transmembrane domain heterodimer and by stabilizing the resulting allb and β3 transmembrane domain homodimers.

Original languageEnglish (US)
Pages (from-to)1424-1429
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number5
DOIs
StatePublished - Feb 1 2005

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Integrin regulation
  • Transmembrane domains
  • αIIbβ3

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