Crystallographic structure of the SH3 domain of the human c‐Yes tyrosine kinase: Loop flexibility and amyloid aggregation

Abstract

SH3 domains from the Src family of tyrosine kinases represent an interesting example of the delicate balance between promiscuity and specificity characteristic of proline-rich ligand recognition by SH3 domains. The development of inhibitors of therapeutic potential requires a good understanding of the molecular determinants of binding affinity and specificity and relies on the availability of high quality structural information. Here, we present the first high-resolution crystal structure of the SH3 domain of the c-Yes oncogen. Comparison with other SH3 domains from the Src family revealed significant deviations in the loop regions. In particular, the n-Src loop, highly flexible and partially disordered, is stabilized in an unusual conformation by the establishment of several intramolecular hydrogen bonds. Additionally, we present here the first report of amyloid aggregation by an SH3 domain from the Src family.

Characterization of Domain–Peptide Interaction Interface: Prediction of SH3 Domain-Mediated Protein–Protein Interaction Network in Yeast by Generic Structure-Based Models

“…Among the 23 class-I SH3 domains, five of them, including Abl (PDB entry: 1bbz), 28 c-Src (1qwf), 29 Hck (2oi3), 30 Fyn (1fyn) 5 and Sho1 (2vkn), 31 had crystal structures complexed with class-I peptides; two of them, including Grb2 (1gbq) 32 and Spta2 (2pqh), 33 had crystal complex structures with class-II peptides; 13 of them had protein crystal structures only (without binding peptides): Itk (1awj), 34 Lyn (1w1f), 35 Myo3 (1ruw), 36 Myo5 (1yp5), 37 Nbp2 (1yn8), 38 P85a (1pht), 39 Sla1_3 (2jt4), 40 Yes (2hda), 41 Lsb3 (1oot), 42 Ysc84 (2a08), 31 Pex13 (1jqq), 43 Bzz1_1 (1zuu), 31 and Bzz1_2 (2a28). 31 For the rest SH3 domains, including Hse1, Rvs167 and Boi1, no crystal structure was available and thus homology modeling was used to model their structures from the scratch.…”

Intertwined dimeric structure for the SH3 domain of the c‐Src tyrosine kinase induced by polyethylene glycol binding

“…The protein was purified by the standard protocol. Protein purity and concentration was determined as described previously [6].…”

“…Initial phasing was performed using Molrep [8]. The coordinates of the c‐Src‐SH3 NMR average models as well as the crystallographic models of the Fyn‐SH3 (unpublished results) and the c‐Yes‐SH3 domain [6], without ligand and water molecules, were used as a search model. No model produced a clear peak although the best results were obtained using the coordinates of the c‐Yes‐SH3 domain, which yields two peaks with a value around 4 σ .…”

Time-Resolved FRET Detection of Subtle Temperature-Induced Conformational Biases in Ensembles of α-Synuclein Molecules

“…[51][52][53] It has also been shown that the αS backbone is highly dynamic at room temperature. 54 Values between 1.6 × 10 − 6 and 52 × 10 − 6 cm 2 /s were calculated for a worm-like chain model of 15-to 132-residue segments, respectively, 55 but the temperature dependence of the backbone dynamics has not been investigated so far.…”