From Binding-Induced Dynamic Effects in SH3 Structures to Evolutionary Conserved Sectors

PLoS Comput Biol. 2016 May 23;12(5):e1004938. doi: 10.1371/journal.pcbi.1004938. eCollection 2016 May.

Abstract

Src Homology 3 domains are ubiquitous small interaction modules known to act as docking sites and regulatory elements in a wide range of proteins. Prior experimental NMR work on the SH3 domain of Src showed that ligand binding induces long-range dynamic changes consistent with an induced fit mechanism. The identification of the residues that participate in this mechanism produces a chart that allows for the exploration of the regulatory role of such domains in the activity of the encompassing protein. Here we show that a computational approach focusing on the changes in side chain dynamics through ligand binding identifies equivalent long-range effects in the Src SH3 domain. Mutation of a subset of the predicted residues elicits long-range effects on the binding energetics, emphasizing the relevance of these positions in the definition of intramolecular cooperative networks of signal transduction in this domain. We find further support for this mechanism through the analysis of seven other publically available SH3 domain structures of which the sequences represent diverse SH3 classes. By comparing the eight predictions, we find that, in addition to a dynamic pathway that is relatively conserved throughout all SH3 domains, there are dynamic aspects specific to each domain and homologous subgroups. Our work shows for the first time from a structural perspective, which transduction mechanisms are common between a subset of closely related and distal SH3 domains, while at the same time highlighting the differences in signal transduction that make each family member unique. These results resolve the missing link between structural predictions of dynamic changes and the domain sectors recently identified for SH3 domains through sequence analysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Computational Biology
  • Computer Simulation
  • Evolution, Molecular
  • Humans
  • Ligands
  • Models, Molecular
  • Mutation
  • Protein Binding
  • Sequence Alignment
  • Thermodynamics
  • src Homology Domains* / genetics

Substances

  • Ligands

Grant support

TL and EC were supported by the Fonds Wetenschappelijk Onderzoek (http://www.fwo.be) grant G.0116.09N (Belgium), a crédit au chercheurs grant number 1.5.081.10 and the project 2.4606.11 from the Fonds de la Recheche Scientifique (http://www.fnrs.be). EC is a postdoctoral researcher with the Belgian Fonds de la Recherche Scientifique (F.R.S.-F.N.R.S. http://www.fnrs.be). IL, AZR and JRS were supported by grants BIO2012-39922-CO2-01, BIO2006-15517-CO2-01 and BIO2009-13261-CO2-01 from the Ministerio de ciencia y Tecnología de España (http://www.mineco.gob.es). AZR was also supported by a Formación de Personal Investigador fellowship also from the Ministerio de ciencia y Tecnología de España (http://www.mineco.gob.es). JRC, JS and FR were supported Vlaams Instituut voor Biotechnologie grant PRJ6 (http://www.vib.be), University of Leuven grant OT/12/092 (http://www.kuleuven.be), the Fonds Wetenschappelijk Onderzoek grant G.0509.13 (http://www.fwo.be) and the Federaal Wetenschapsbeleid (http://www.belspo.be) Interuniversitaire Attractiepool grant P7/16. JS is also supported by the European Research Council under the European Union's Horizon 2020 Framework Programme, ERC Grant agreement 647458 (MANGO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.