Functional insights from the molecular modelling of a novel two-component system

Functional insights from the molecular modelling of a novel two-component system Two-component systems (TCSs) are the major signalling pathway in bacteria and represent potential drug targets. Among the 11 paired TCS proteins present in Mycobacterium tuberculosis H37Rv, the histidine kinases (HKs) Rv0600c (HK1) and Rv0601c (HK2) are annotated to phosphorylate one response regulator (RR) Rv0602c (TcrA). We wanted to establish the sequence-structure–function relationship to elucidate the mechanism of phosphotransfer using in silico methods. Sequence alignments and codon usage analysis showed that the two domains encoded by a single gene in homologous HKs have been separated into individual open-reading frames in M. tuberculosis . This is the first example where two incomplete HKs are involved in phosphorylating a single RR. The model shows that HK2 is a unique histidine phosphotransfer (HPt)-mono-domain protein, not found as lone protein in other bacteria. The secondary structure of HKs was confirmed using “far-UV” circular dichroism study of purified proteins. We propose that HK1 phosphorylates HK2 at the conserved H 131 and the phosphoryl group is then transferred to D 73 of TcrA. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Biochemical and Biophysical Research Communications Elsevier

Functional insights from the molecular modelling of a novel two-component system

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Publisher
Elsevier
Copyright
Copyright © 2006 Elsevier Inc.
ISSN
0006-291x
DOI
10.1016/j.bbrc.2006.04.019
Publisher site
See Article on Publisher Site

Abstract

Two-component systems (TCSs) are the major signalling pathway in bacteria and represent potential drug targets. Among the 11 paired TCS proteins present in Mycobacterium tuberculosis H37Rv, the histidine kinases (HKs) Rv0600c (HK1) and Rv0601c (HK2) are annotated to phosphorylate one response regulator (RR) Rv0602c (TcrA). We wanted to establish the sequence-structure–function relationship to elucidate the mechanism of phosphotransfer using in silico methods. Sequence alignments and codon usage analysis showed that the two domains encoded by a single gene in homologous HKs have been separated into individual open-reading frames in M. tuberculosis . This is the first example where two incomplete HKs are involved in phosphorylating a single RR. The model shows that HK2 is a unique histidine phosphotransfer (HPt)-mono-domain protein, not found as lone protein in other bacteria. The secondary structure of HKs was confirmed using “far-UV” circular dichroism study of purified proteins. We propose that HK1 phosphorylates HK2 at the conserved H 131 and the phosphoryl group is then transferred to D 73 of TcrA.

Journal

Biochemical and Biophysical Research CommunicationsElsevier

Published: Jun 16, 2006

References

  • Probing catalytically essential domain orientation in histidine kinase EnvZ by targeted disulfide crosslinking
    Cai, S.J.; Khorchid, A.; Ikura, M.; Inouye, M.
  • An essential role for PhoP in Mycobacterium tuberculosis virulence
    Perez, E.; Samper, S.; Bordas, Y.; Guilhot, C.; Gicquel, B.; Martin, C.
  • Transphosphorylation of the TorR response regulator requires the three phosphorylation sites of the TorS unorthodox sensor in Escherichia coli
    Jourlin, C.; Ansaldi, M.; Mejean, V.
  • The Jalview Java alignment editor
    Clamp, M.; Cuff, J.; Searle, S.M.; Barton, G.J.
  • GenTHREADER: An efficient and reliable protein fold recognition method for genomic sequences
    Jones, D.T.
  • Automated docking using a lamarckian genetic algorithm and empirical binding free energy function
    Morris, G.M.; Goodsell, D.S.; Halliday, R.S.; Huey, R.; Hart, W.E.; Belew, R.K.; Olson, A.J.
  • DICHROWEB: A website for the analysis of protein secondary structure from circular dichroism spectra
    Lobley, A.; Wallace, B.A.
  • Specificity of the BvgAS and EvgAS phosphorelay is mediated by the C-terminal HPt domains of the sensor proteins
    Perraud, A.-L.; Kimmel, B.; Weiss, V.; Gross, R.

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