title: Thermodynamic contribution of backbone conformational entropy in the binding between SH3 domain and proline-rich motif.
abstract: Biological functions of intrinsically disordered proteins (IDPs), and proteins containing intrinsically disordered regions (IDRs) are often mediated by short linear motifs, like proline-rich motifs (PRMs). Upon binding to their target proteins, IDPs undergo a disorder-to-order transition which is accompanied by a large conformational entropy penalty. Hence, the molecular mechanisms underlying control of conformational entropy are critical for understanding the binding affinity and selectivity of IDPs-mediated protein-protein interactions (PPIs). Here, we investigated the backbone conformational entropy change accompanied by binding of the N-terminal SH3 domain (nSH3) of CrkII and PRM derived from guanine nucleotide exchange factor 1 (C3G). In particular, we focused on the estimation of conformational entropy change of disordered PRM upon binding to the nSH3 domain. Quantitative characterization of conformational dynamics of disordered peptides like PRMs is limited. Hence, we combined various methods, including NMR model-free analysis, δ2D, DynaMine, and structure-based calculation of entropy loss. This study demonstrates that the contribution of backbone conformational entropy change is significant in the PPIs mediated by IDPs/IDRs.
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Danyun
authors.initials: D
authors.lastname: Zeng
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Qingliang
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA. Electronic address: jaehyuncho@tamu.edu.
authors.forename: Jae-Hyun
authors.initials: JH
authors.lastname: Cho
mesh_terms: D019277:Entropy; D064267:Intrinsically Disordered Proteins / Q000737:chemistry*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D011392:Proline / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D013816:Thermodynamics; D018909:src Homology Domains
chemical_list: D064267:Intrinsically Disordered Proteins; D008024:Ligands; D011392:Proline
keywords: Conformational entropy; Intrinsically disordered proteins; Proline-rich motif; Protein-protein interactions; SH3 domain