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New insights into the activation of Escherichia coli tyrosine kinase revealed by molecular dynamics simulation and biochemical analysis.

Abstract：

:Escherichia coli tyrosine kinase (Etk) regulates the export of pathogenic capsular polysaccharide (CPS) by intermolecularly autophosphorylating its C-terminal tyrosine cluster. The kinase Etk, however, needs to be first activated by the intramolecular phosphorylation of a tyrosine residue, Y574, next to the active site. The recently determined structure of Etk shows that dephosphorylated Y574 blocks the active site and prevents substrate access. After phosphorylation, the negatively charged P-Y574 side chain was previously postulated to flip out to associate with a positively charged R614, unblocking the active site. This proposed activation is unique among protein kinases; however, there is no direct structural evidence in support of this hypothesis. In this paper, we carried out molecular dynamics simulation, mutagenesis, and biochemical analysis to study the activation mechanism of Etk. Our simulation results are in excellent agreement with the proposed molecular switch involving P-Y574 and R614 in the activation of Etk. Further, we show that a previously unidentified residue, R572, modulates the rotation of the P-Y574 side chain through electrostatic interaction, slowing down the opening of the active site. Our enzymatic assays demonstrate that the R572A mutant of Etk possesses significantly increased kinase activity, providing direct experimental support for the unique activation mechanism of Etk. In addition, the simulation of the Etk Y574F mutant predicted short periods of unblocked active site by Y574F, in good agreement with the low kinase activity of this mutant. The C-terminal substrate peptide and the nucleotide cofactor were also docked into the active site, and their implications are discussed.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Lu T,Tan H,Lee D,Chen G,Jia Z

doi

10.1021/bi900811p

subject

Has Abstract

pub_date

2009-08-25 00:00:00

pages

7986-95

issue

33

eissn

0006-2960

issn

1520-4995

journal_volume

48

pub_type

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