Integrin Conformational Regulation: Uncoupling Extension/Tail Separation from Changes in the Head Region by a Multiresolution Approach

Mattia Rocco, Camillo Rosano, John W. Weisel, David A. Horita, Roy R. Hantgan

Research output: Contribution to journalArticle

Abstract

Integrin-dependent adhesion and signaling are regulated by conformational changes whose details remain controversial. Crystallography revealed bent shapes for resting and primed integrin ectodomains, whereas large, ligand-induced rearrangements in other constructs suggested extension, "opening," and tail separation. We have used experimental/computed hydrodynamics to discriminate among different αvβ3 and αIIbβ3 atomic models built on X-ray, NMR, and EM data. In contrast with X-ray structures and EM maps, hydrodynamics indicate that resting integrins are already extended. Furthermore, the hydrodynamics of an αvβ3 ectodomain-fibronectin fragment complex support opening via additional head region conformational changes (hybrid domain swing-out), but without tail separation. Likewise, frictional changes induced by priming agents in full-length αIIbβ3 correlate well with the swing-out coupled to a simple transmembrane helix shift in an extended, electron tomography-based model. Extension and immediate tail separation are then uncoupled from head region rearrangements following activation, thus underscoring integrins' delicate, finely tuned plasticity.

Original languageEnglish
Pages (from-to)954-964
Number of pages11
JournalStructure
Volume16
Issue number6
DOIs
Publication statusPublished - Jun 11 2008

Keywords

  • CELLBIO
  • PROTEINS

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

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