MRC National Institute for Medical Research, London
Science for Health
FHA domain binding capacity and regulatory functions
26 March 2009
Forkhead-associated (FHA) domains have gained considerable prominence as ubiquitous phosphothreonine-dependent binding modules. Their precise roles in serine and threonine kinase (STK) pathways and mechanisms of regulation remain unclear.
Steve Smerdon (pictured) and his team, from NIMR's Division of Molecular Structure, in collaboration with Geoff Kelly from the MRC Biomedical NMR Centre and Roger Buxton from NIMR's Division of Mycobacterial Research, have been investigating Rv1827, an FHA domain–containing protein from Mycobacterium tuberculosis. They have derived a complete molecular description of an FHA-mediated STK signaling process that, remarkably, involves phospho-independent interactions with at least three distinct metabolic enzyme complexes. These interactions occur through a common surface which is occluded by a novel intra-molecular phospho-dependent binding of the Rv1827 FHA domain to its own N-terminal region following phosphorylation by either of two Mycobacterium tuberculosis protein kinases.
Dr Smerdon said:
This work is exciting from several viewpoints. It clearly shows that FHA domains are not the 'one trick ponies' that many, including ourselves, had assumed from earlier studies and shows that their interactions may not always depend on prior phosphorylation of binding partners. Satisfyingly, Rv1827 binding to all three enzyme complexes is still regulated by a nonetheless unusual phosphothreonine-dependent interaction with its regulatory region. This happens in response to the activities of at least two different kinases, called pknB and pknG. So a small protein with a rather simple architecture is able to integrate inputs from two upstream regulators and disseminate these signals to at least three different effector molecules. In a broader sense, our data show that these ubiquitous signaling domains are likely to be functioning in many different ways in different cellular contexts - something we really didn't expect!
Original article
The research findings are published in full in:
Timothy J. Nott, Geoff Kelly, Lasse Stach, Jiejin Li, Sarah Westcott, Dony Patel, Debbie M. Hunt, Steven Howell, Roger S. Buxton, Helen M. O’Hare, and Stephen J. Smerdon. (2009)
An Intramolecular Switch Regulates Phosphoindependent FHA Domain Interactions in Mycobacterium tuberculosis
Science Signaling 2, ra12. Publisher abstract
There is also a podcast about the article on the Science Signaling website.
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