Ligand binding promotes the entropy-driven oligomerization of integrin αIIbβ3

Roy R. Hantgan, Douglas S. Lyles, T. Conn Mallett, Mattia Rocco, Chandrasekaran Nagaswami, John W. Weisel

Research output: Contribution to journalArticle

Abstract

Integrin αIIbβ3 clusters on the platelet surface after binding adhesive proteins in a process that regulates signal transduction. However, the intermolecular forces driving integrin self-association are poorly understood. This work provides new insights into integrin clustering mechanisms by demonstrating how temperature and ligand binding interact to affect the oligomeric state of αIIbβ3. The ligand-free receptor, solubilized in thermostable octyl glucoside micelles, exhibited a cooperative transition at ∼43°C, monitored by changes in intrinsic fluorescence and circular dichroism. Both signals changed in a direction opposite to that for global unfolding, and both were diminished upon binding the fibrinogen γ-chain ligand-mimetic peptide cHArGD. Free and bound receptors also exhibited differential sensitivity to temperature-enhanced oligomerization, as measured by dynamic light scattering, sedimentation velocity, and sedimentation equilibrium. Van't Hoff analyses of dimerization constants for αIIbβ3 complexed with cHArGD, cRGD, or eptifibatide yielded large, favorable entropy changes partly offset by unfavorable enthalpy changes. Transmission electron microscopy showed that ligand binding and 37°C incubation enhanced assembly of integrin dimers and larger oligomers linked by tail-to-tail contacts. Interpretation of these images was aided by threading models for αIIbβ3 protomers and dimers based on the ectodomain structure of αvβ3. We propose that entropy-favorable nonpolar interactions drive ligand-induced integrin clustering and outside-in signaling.

Original languageEnglish
Pages (from-to)3417-3426
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number5
DOIs
Publication statusPublished - Jan 31 2003

ASJC Scopus subject areas

  • Biochemistry

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    Hantgan, R. R., Lyles, D. S., Mallett, T. C., Rocco, M., Nagaswami, C., & Weisel, J. W. (2003). Ligand binding promotes the entropy-driven oligomerization of integrin αIIbβ3 . Journal of Biological Chemistry, 278(5), 3417-3426. https://doi.org/10.1074/jbc.M208869200