Solution properties of full-length integrin αiIbβ 3 refined models suggest environment-dependent induction of alternative bent/extended resting states

Camillo Rosano, Mattia Rocco

Research output: Contribution to journalArticlepeer-review

Abstract

The recently published novel integrin αIIbβ 3 ectodomain crystallographic structure and NMR structures of its transmembrane/cytoplasmic segments were employed to refine previously developed molecular models. Alternative complete αIIbβ3 models were built and evaluated, and their shape was compared with EM maps and their computed hydrodynamic/conformational properties were compared with the available experimental data. A partially extended/closed model, or a mixture of bent/closed and extended/closed conformations, are both compatible with the results of a recent small-angle neutron scattering study of Triton X-100-solubilized resting αIIbβ3, while new electron microscopy evidence of nanodiscs-embedded αIIbβ 3 supports the bent/closed resting form. However, only an extended/closed model matches well the hydrodynamics of either octyl-glucoside-solubilized or nanodiscs-embedded resting α IIbβ3, suggesting that different solubilization strategies and substrate interactions might operate a conformational selection between alternative, stable states. Furthermore, extended/open models are required to match the electron tomography map and the hydrodynamics following the priming-induced β3 hybrid domain swing-out, but without immediate full tail separation. Importantly, both extension and opening transitions can occur by pivoting at the recently identified β3 hinge point, which does not appear to be freely flexible. The structure and mechanism of action of integrins thus seem to depend on discrete transitions and to be more tightly coupled to the local environment than previously thought.

Original languageEnglish
Pages (from-to)3190-3202
Number of pages13
JournalFEBS Journal
Volume277
Issue number15
DOIs
Publication statusPublished - Aug 2010

Keywords

  • blood coagulation
  • hydrodynamics
  • modeling
  • modular proteins
  • protein structure

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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