Cargando…

The impact of oncogenic mutations of the viral Src kinase on the structure and stability of the SH3 domain

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 a...

Descripción completa

Detalles Bibliográficos
Autores principales: Salinas-Garcia, M. Carmen, Plaza-Garrido, Marina, Camara-Artigas, Ana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Union of Crystallography 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171063/
https://www.ncbi.nlm.nih.gov/pubmed/34076598
http://dx.doi.org/10.1107/S2059798321004344
_version_ 1783702358586294272
author Salinas-Garcia, M. Carmen
Plaza-Garrido, Marina
Camara-Artigas, Ana
author_facet Salinas-Garcia, M. Carmen
Plaza-Garrido, Marina
Camara-Artigas, Ana
author_sort Salinas-Garcia, M. Carmen
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8171063
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher International Union of Crystallography
record_format MEDLINE/PubMed
spelling pubmed-81710632021-06-14 The impact of oncogenic mutations of the viral Src kinase on the structure and stability of the SH3 domain Salinas-Garcia, M. Carmen Plaza-Garrido, Marina Camara-Artigas, Ana Acta Crystallogr D Struct Biol Research Papers 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. International Union of Crystallography 2021-05-19 /pmc/articles/PMC8171063/ /pubmed/34076598 http://dx.doi.org/10.1107/S2059798321004344 Text en © M. Carmen Salinas-Garcia et al. 2021 https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
spellingShingle Research Papers
Salinas-Garcia, M. Carmen
Plaza-Garrido, Marina
Camara-Artigas, Ana
The impact of oncogenic mutations of the viral Src kinase on the structure and stability of the SH3 domain
title The impact of oncogenic mutations of the viral Src kinase on the structure and stability of the SH3 domain
title_full The impact of oncogenic mutations of the viral Src kinase on the structure and stability of the SH3 domain
title_fullStr The impact of oncogenic mutations of the viral Src kinase on the structure and stability of the SH3 domain
title_full_unstemmed The impact of oncogenic mutations of the viral Src kinase on the structure and stability of the SH3 domain
title_short The impact of oncogenic mutations of the viral Src kinase on the structure and stability of the SH3 domain
title_sort impact of oncogenic mutations of the viral src kinase on the structure and stability of the sh3 domain
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171063/
https://www.ncbi.nlm.nih.gov/pubmed/34076598
http://dx.doi.org/10.1107/S2059798321004344
work_keys_str_mv AT salinasgarciamcarmen theimpactofoncogenicmutationsoftheviralsrckinaseonthestructureandstabilityofthesh3domain
AT plazagarridomarina theimpactofoncogenicmutationsoftheviralsrckinaseonthestructureandstabilityofthesh3domain
AT camaraartigasana theimpactofoncogenicmutationsoftheviralsrckinaseonthestructureandstabilityofthesh3domain
AT salinasgarciamcarmen impactofoncogenicmutationsoftheviralsrckinaseonthestructureandstabilityofthesh3domain
AT plazagarridomarina impactofoncogenicmutationsoftheviralsrckinaseonthestructureandstabilityofthesh3domain
AT camaraartigasana impactofoncogenicmutationsoftheviralsrckinaseonthestructureandstabilityofthesh3domain