SH3 domains are small protein modules involved in the regulation of important cellular pathways. These domains mediate protein-protein interactions recognizing motifs rich in proline on the target protein. The SH3 domain from Grb2 (Grb2-SH3) presents the typical structure of an SH3 domain composed of two-three stranded antiparallel β-sheets orthogonally packed onto each other, to form a single hydrophobic core. Grb2 interacts, via SH3 domain, with Gab2, a scaffolding disordered protein, triggering some key metabolic pathways involved in cell death and differentiation. In this work we report a mutational analysis (φ-value analysis) of the folding pathway of Grb2-SH3 that, coupled with molecular dynamic simulations, allows us to assess the structure of the transition state and the mechanism of folding of this domain. Data suggest that Grb2-SH3 folds via a native-like, diffused transition state with a concurrent formation of native-like secondary and tertiary structure (nucleation-condensation mechanism) and without the accumulation of folding intermediates. The comparison between our data and previous folding studies on SH3 domains belonging to other proteins, highlights that proteins of this class may fold via alternative pathways, stabilized by different nuclei leading or not to accumulation of folding intermediates. This comparative analysis suggests that the alternative folding pathways for this class of SH3 domains can be selectively regulated by the specific aminoacid sequences.
The Folding Mechanism of the SH3 Domain from Grb2 / F. Troilo, D. Bonetti, C. Camilloni, A. Toto, S. Longhi, M. Brunori, S. Gianni. - In: JOURNAL OF PHYSICAL CHEMISTRY. B, CONDENSED MATTER, MATERIALS, SURFACES, INTERFACES & BIOPHYSICAL. - ISSN 1520-6106. - 122:49(2018 Dec 13), pp. 11166-11173.
|Titolo:||The Folding Mechanism of the SH3 Domain from Grb2|
|Settore Scientifico Disciplinare:||Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)|
Settore BIO/10 - Biochimica
|Data di pubblicazione:||13-dic-2018|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1021/acs.jpcb.8b06320|
|Appare nelle tipologie:||01 - Articolo su periodico|