Network approach of the conformational change of c-Src, a tyrosine kinase, by molecular dynamics simulation

Hyun Jung Yoon,Sungmin Lee,Sangwook Wu,Sun Joo Park

doi:10.1038/s41598-018-23964-5

Hyun Jung Yoon, Sungmin Lee + Show 2 more

Open Access

https://doi.org/10.1038/s41598-018-23964-5

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Abstract

Non-receptor tyrosine kinase c-Src plays a critical role in numerous cellular signalling pathways. Activation of c-Src from its inactive to the active state involves large-scale conformational changes, and is controlled by the phosphorylation state of two major phosphorylation sites, Tyr416 and Tyr527. A detailed mechanism for the entire conformational transition of c-Src via phosphorylation control of Tyr416 and Tyr527 is still elusive. In this study, we investigated the inactive-to-active conformational change of c-Src by targeted molecular dynamics simulation. Based on the simulation, we proposed a dynamical scenario for the activation process of c-Src. A detailed study of the conformational transition pathway based on network analysis suggests that Lys321 plays a key role in the c-Src activation process.

Highlights

The Src family of non-receptor tyrosine kinases includes c-Src, Fyn, Yes, Blk, Yrk, Fgr, Hck, Lck and Lyn[1]
Dephosphorylation of pTyr[527] releases the closed c-Src conformation, resulting in the activation of the Src homology 3 (SH3), SH2 and tyrosine kinase domains together with an autophosphorylation of Tyr[416]. This autophosphorylation at Tyr[416], which is located in the activation loop of the tyrosine kinase domain, is another essential event in the process
Utilised three centrality measures – the betweenness, closeness and degree centralities – to reveal the important residues controlling the conformational transition of the c-Src protein between the inactive and active conformations, using molecular dynamics simulation

Summary

Introduction

The Src family of non-receptor tyrosine kinases includes c-Src, Fyn, Yes, Blk, Yrk, Fgr, Hck, Lck and Lyn[1]. A major phosphorylation site is Tyr[527], which is present in the C-terminal tail of c-Src, but not in v-Src. Dephosphorylation of pTyr[527] releases the closed c-Src conformation, resulting in the activation of the SH3, SH2 and tyrosine kinase domains together with an autophosphorylation of Tyr[416]. Dephosphorylation of pTyr[527] releases the closed c-Src conformation, resulting in the activation of the SH3, SH2 and tyrosine kinase domains together with an autophosphorylation of Tyr[416] This autophosphorylation at Tyr[416], which is located in the activation loop of the tyrosine kinase domain, is another essential event in the process. Utilised three centrality measures – the betweenness, closeness and degree centralities – to reveal the important residues controlling the conformational transition of the c-Src protein between the inactive and active conformations, using molecular dynamics simulation

Methods

Results

Conclusion