Imidazole as a Small Molecule Analogue in Two-Component Signal Transduction

Page, Stephani C.; Silversmith, Ruth E.; Collins, Edward J.; Bourret, Robert B.

doi:10.1021/acs.biochem.5b01082

Title: Imidazole as a Small Molecule Analogue in Two-Component Signal Transduction

Journal Article · Wed Dec 02 00:00:00 EST 2015 · Biochemistry

DOI:https://doi.org/10.1021/acs.biochem.5b01082· OSTI ID:1245858

Page, Stephani C. ^[1]; Silversmith, Ruth E. ^[1]; Collins, Edward J. ^[1]; Bourret, Robert B. ^[1]

Univ. of North Carolina, Chapel Hill, NC (United States)

In two-component signal transduction systems (TCSs), responses to stimuli are mediated through phosphotransfer between protein components. Canonical TCSs use His → Asp phosphotransfer in which phosphoryl groups are transferred from a conserved His on a sensory histidine kinase (HK) to a conserved Asp on a response regulator (RR). RRs contain the catalytic core of His → Asp phosphotransfer, evidenced by the ability of RRs to autophosphorylate with small molecule analogues of phospho-His proteins. Phosphorelays are a more complex variation of TCSs that additionally utilize Asp → His phosphotransfer through the use of an additional component, the histidine-containing phosphotransfer domain (Hpt), which reacts with RRs both as phosphodonors and phosphoacceptors. Here we show that imidazole has features of a rudimentary Hpt. Imidazole acted as a nucleophile and attacked phosphorylated RRs (RR-P) to produce monophosphoimidazole (MPI) and unphosphorylated RR. Phosphotransfer from RR-P to imidazole required the intact RR active site, indicating that the RR provided the core catalytic machinery for Asp → His phosphotransfer. Imidazole functioned in an artificial phosphorelay to transfer phosphoryl groups between unrelated RRs. The X-ray crystal structure of an activated RR·imidazole complex showed imidazole oriented in the RR active site similarly to the His of an Hpt. Furthermore, imidazole interacted with RR nonconserved active site residues, which influenced the relative reactivity of RR-P with imidazole versus water. Rate constants for reaction of imidazole or MPI with chimeric RRs suggested that the RR active site contributes to the kinetic preferences exhibited by the YPD1 Hpt.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH)

Grant/Contract Number:: R01 GM050860; T32 GM008570

OSTI ID:: 1245858

Journal Information:: Biochemistry, Vol. 54, Issue 49; ISSN 0006-2960

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 8 works

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Title: Imidazole as a Small Molecule Analogue in Two-Component Signal Transduction

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