Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Sci. Signal., 24 March 2009
Vol. 2, Issue 63, p. ra12
[DOI: 10.1126/scisignal.2000212]

RESEARCH

An Intramolecular Switch Regulates Phosphoindependent FHA Domain Interactions in Mycobacterium tuberculosis

Timothy J. Nott1, Geoff Kelly2, Lasse Stach1, Jiejin Li1, Sarah Westcott1, Dony Patel1, Debbie M. Hunt3, Steven Howell1, Roger S. Buxton3, Helen M. O’Hare4,5, and Stephen J. Smerdon1*

1 Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
2 Biomedical NMR Centre, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
3 Division of Mycobacterial Research, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
4 Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE1 9HN, UK.
5 Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK.

Abstract: Forkhead-associated (FHA) domains have gained considerable prominence as ubiquitous phosphothreonine-dependent binding modules; however, their precise roles in serine and threonine kinase (STK) pathways and mechanisms of regulation remain unclear. From experiments with Rv1827, an FHA domain–containing protein from Mycobacterium tuberculosis, we derived a complete molecular description of an FHA-mediated STK signaling process. First, binding of the FHA domain to each of three metabolic enzyme complexes regulated their catalytic activities but did not require priming phosphorylation. However, phosphorylation of a threonine residue within a conserved amino-terminal motif of Rv1827 triggered its intramolecular association with the FHA domain of Rv1827, thus blocking its interactions with each of the three enzymes. The solution structure of this inactivated form and further mutagenic studies showed how a previously unidentified intramolecular phosphoswitch blocked the access of the target enzymes to a common FHA interaction surface and how this shared surface accommodated three functionally related, but structurally diverse, binding partners. Thus, our data reveal an unsuspected versatility in the FHA domain that allows for the transformation of multiple kinase inputs into various downstream regulatory signals.

* To whom correspondence should be addressed. E-mail: stephen.smerdon{at}nimr.mrc.ac.uk

Citation: T. J. Nott, G. Kelly, L. Stach, J. Li, S. Westcott, D. Patel, D. M. Hunt, S. Howell, R. S. Buxton, H. M. O’Hare, S. J. Smerdon, An Intramolecular Switch Regulates Phosphoindependent FHA Domain Interactions in Mycobacterium tuberculosis. Sci. Signal. 2, ra12 (2009).

Read the Full Text

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Forkhead-associated Domain-containing Protein Rv0019c and Polyketide-associated Protein PapA5, from Substrates of Serine/Threonine Protein Kinase PknB to Interacting Proteins of Mycobacterium tuberculosis.
M. Gupta, A. Sajid, G. Arora, V. Tandon, and Y. Singh (2009)
J. Biol. Chem. 284, 34723-34734
   Abstract »    Full Text »    PDF »
A Biosensor for Fluorescent Determination of ADP with High Time Resolution.
S. Kunzelmann and M. R. Webb (2009)
J. Biol. Chem. 284, 33130-33138
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 24 March 2009.
S. J. Smerdon and A. M. VanHook (2009)
Science Signaling 2, pc6
   Abstract »    Full Text »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882