There is a growing interest in understanding the properties of intrinsically disordered proteins (IDPs); however, the characterization of these states remains an open challenge. IDPs appear to have functional roles that diverge from those of folded proteins and revolve around their ability to act as hubs for protein-protein interactions. To gain a better understanding of the modes of binding of IDPs, we combined statistical mechanics, calorimetry, and NMR spectroscopy to investigate the recognition and binding of a fragment from the disordered protein Gab2 by the growth factor receptor-bound protein 2 (Grb2), a key interaction for normal cell signaling and cancer development. Structural ensemble refinement by NMR chemical shifts, thermodynamics measurements, and analysis of point mutations indicated that the population of preexisting bound conformations in the free-state ensemble of Gab2 is an essential determinant for recognition and binding by Grb2. A key role was found for transient polyproline II (PPII) structures and extended conformations. Our findings are likely to have very general implications for the biological behavior of IDPs in light of the evidence that a large fraction of these proteins possess a specific propensity to form PPII and to adopt conformations that are more extended than the typical random-coil states.
Conformational recognition of an intrinsically disordered protein / J..M. Krieger, G. Fusco, M. Lewitzky, P..C. Simister, J. Marchant, C. Camilloni, S..M. Feller, A. De Simone. - In: BIOPHYSICAL JOURNAL. - ISSN 0006-3495. - 106:8(2014), pp. 1771-1779.
|Titolo:||Conformational recognition of an intrinsically disordered protein|
|Parole Chiave:||Adaptor Proteins, Signal Transducing; Amino Acid Sequence; GRB2 Adaptor Protein; Intrinsically Disordered Proteins; Molecular Dynamics Simulation; Molecular Sequence Data; Mutant Proteins; Peptides; Point Mutation; Protein Binding; src Homology Domains; Biophysics|
|Settore Scientifico Disciplinare:||Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)|
|Data di pubblicazione:||2014|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.bpj.2014.03.004|
|Appare nelle tipologie:||01 - Articolo su periodico|