The impact of oncogenic mutations of the viral Src kinase on the structure and stability of the SH3 domain. Issue 6 (24th May 2021)

• Record Type: Journal Article
• Authors: Salinas-Garcia, M. Carmen; Plaza-Garrido, Marina; Camara-Artigas, Ana
• Is Part Of: Acta crystallographica. Volume 77:Issue 6(2021)
• Page Start: 854
• Page End: 866
• Publication Date: 2021-05-24
• Subjects: SH3 domain -- Src kinase -- tyrosine kinases -- intertwined dimer -- oncogens -- crystal structure; X-ray crystallography -- Periodicals; Crystallography -- Periodicals; Molecular biology -- Periodicals; Molecular structure -- Periodicals; Biomolecules -- Structure -- Periodicals; Cytology -- Periodicals; Biomolecules -- Structure; Crystallography; Cytology; Molecular biology; Molecular structure; X-ray crystallography; Periodicals; 548
• DOI: 10.1107/S2059798321004344
• Languages: English
• ISSNs: 2059-7983

Abstract

Abstract : The crystal structures of three viral Src kinase (v‐Src) SH3‐domain variants have been determined in order to obtain insights into the roles of these oncogenic mutations in the function of v‐Src. Abstract : Src kinase belongs to the family of Src‐related nonreceptor tyrosine kinases. Because of its physiological role in cell growth and proliferation, its activity is strictly controlled by several mechanisms. Nevertheless, in viral Src kinase (v‐Src) some of these mechanisms fail, and its uncontrolled activity is responsible for the occurrence of cancer. Here, the crystal structures of three SH3‐domain mutants of v‐Src were determined to unveil the effects of these oncogenic mutations in this regulatory domain. Mutations in the n‐Src and distal loops have a low impact on the overall structure of the domain and its capacity to form intertwined dimers. However, mutations in the RT loop compromise the stability of the domain and make the protein very prone to aggregation. Additionally, these mutations prevent the formation of intertwined dimers. The results show a synergistic effect between mutations in the RT loop and those in the n‐Src and distal loops. Analysis of the structures of the v‐Src SH3‐domain mutants and the closed inactive conformation of cellular Src kinase (c‐Src) point to a loss of the interactions that are required to establish the compact inactive form of the kinase. Nevertheless, an analysis of structures of the c‐Src SH3 domain complexed with class I and II peptides points to minor changes in the interactions between the v‐Src SH3 domain and these peptides. In this way, the structures reported here indicate that mutations in the RT loop might impair the kinase regulation mechanism without affecting the recognition of short proline‐rich motifs in the target proteins of the kinase, thus explaining the oncogenic behaviour of the protein.