The N-terminal end of the catalytic domain of SRC kinase Hck is a conformational switch implicated in long-range allosteric regulation.
Signal transduction in cell growth and proliferation involves regulation of kinases through long-range allostery between remote protein regions. Molecular dynamics free energy calculations are used to clarify the coupling between the catalytic domain of Src kinase Hck and its N-terminal end connecting to the regulatory SH2 and SH3 modules. The N-terminal end is stable in the orientation required for the regulatory modules to remain properly bound only in the inactive catalytic domain. In the active catalytic domain, the N-terminal end prefers a different conformation consistent with dissociation of the regulatory modules. The free energy surface shows that the N-terminal end acts as a reversible two-state conformational switch coupling the catalytic domain to the regulatory modules. Structural analogy with insulin receptor kinase and c-Src suggests that such reversible conformational switching in a critical hinge region could be a common mechanism in long-range allosteric regulation of protein kinase activity.
Banavali
Nilesh K
NK
Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York 10021, USA.
Roux
Benoît
B
D000494:Allosteric Regulation; D000818:Animals; D030161:Avian Proteins / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D002645:Chickens; D006801:Humans; D007700:Kinetics; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D051572:Proto-Oncogene Proteins c-hck / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics; D013997:Time Factors
D030161:Avian Proteins; D010446:Peptide Fragments; D051572:Proto-Oncogene Proteins c-hck