Solution properties of full-length integrin alpha(IIb)beta3 refined models suggest environment-dependent induction of alternative bent /extended resting states.
The recently published novel integrin alpha(IIb)beta(3) ectodomain crystallographic structure and NMR structures of its transmembrane/cytoplasmic segments were employed to refine previously developed molecular models. Alternative complete alpha(IIb)beta(3) 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 alpha(IIb)beta(3), while new electron microscopy evidence of nanodiscs-embedded alpha(IIb)beta(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 alpha(IIb)beta(3), 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 beta(3) hybrid domain swing-out, but without immediate full tail separation. Importantly, both extension and opening transitions can occur by pivoting at the recently identified beta(3) 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.
Rosano
Camillo
C
Nanobiotecnologie, Istituto Nazionale per la Ricerca sul Cancro (IST), Genova, Italy.
Rocco
Mattia
M
D019295:Computational Biology; D006801:Humans; D008958:Models, Molecular; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry*; D018583:Pliability; D011487:Protein Conformation; D012996:Solutions
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D012996:Solutions