Integrin conformational regulation: uncoupling extension/tail separation from changes in the head region by a multiresolution approach.
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 alpha(v)beta(3) and alpha(IIb)beta(3) 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 alpha(v)beta(3) 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 alpha(IIb)beta(3) 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.
Rocco
Mattia
M
S.S. Biopolimeri e Proteomica, Istituto Nazionale per la Ricerca sul Cancro, IST c/o CBA, Genoa, Italy. mattia.rocco@istge.it
Rosano
Camillo
C
Weisel
John W
JW
Horita
David A
DA
Hantgan
Roy R
RR
D018360:Crystallography, X-Ray; D005353:Fibronectins / Q000737:chemistry; D039302:Integrin alphaVbeta3 / Q000737:chemistry* / Q000648:ultrastructure; D036341:Intercellular Signaling Peptides and Proteins; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry* / Q000648:ultrastructure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014867:Water / Q000737:chemistry
D005353:Fibronectins; D039302:Integrin alphaVbeta3; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014867:Water; C057986:echistatin