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An active‐like Src conformation explains its dynamic regulation
Author(s) -
Ahuja Lalima G,
Meng Yilin,
Kornev Alexandr P,
Roux Benoit,
Taylor Susan
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.lb149
Subject(s) - allosteric regulation , proto oncogene tyrosine protein kinase src , protein kinase domain , kinase , mutant , microbiology and biotechnology , chemistry , biochemistry , tyrosine kinase , sh3 domain , biology , biophysics , signal transduction , enzyme , gene
Biological signaling by protein kinases plays an essential role in cellular function. The switch between inactive and active protein kinase conformations is central to their regulation. The active conformations of protein kinases are triggered and maintained by various post‐translational modifications. The inactive conformation of Src tyrosine kinase has a non‐phosphorylated activation loop and a rolled‐out αC helix. The R‐spine at the Src kinase core is disassembled via the RS3 residue when the αC helix is disengaged. Maneuvering of the C‐spine is crucial for obtaining a pseudokinase conformation of Src that could be crucial for exploring its scaffolding functions. Our Umbrella sampling methods allow for mapping the conformational landscape of the Src kinase domain and characterizing four defining states; the inactive, active conformations and two intermediates. Mutation of the C‐spine V281F allows for the closing of the two kinase lobes in the absence of ATP. An allosteric region at the β3‐αC loop allows for engaging the αC helix and the RS3 residue of the R‐spine via the L297F mutation. The L297F/ V281F double mutant allows for stabilization of a unique catalytically dead kinase conformation in the active‐like state. These studies allow for exploration of active‐like Src kinase states that define both the underlying kinase activation switch and the dynamic allostery in the molecular communication at the kinase core. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .