MRC National Institute for Medical Research, London
Science for Health
Signaling conundrums solved
09 December 2010
Over the last 10 years or so it has emerged that phosphorylation-dependent protein-protein interactions, once thought to be the preserve of tyrosine kinase pathways, play a central role in Ser/Thr kinase signalling. These developments have proceeded hand-in-hand with the identification of a structurally unrelated family of proteins and domains that are able to specifically recognise phosphoserine or phosphothreonine- containing epitopes in their binding partners. In this way, phosphorylation becomes a reversible switch for signalling complex assembly.
Among these domains, one of the earliest identified was the Forkhead-associated or FHA domain. Proteins containing these binding modules function in many cellular systems, not just in eukaryotes but in many prokaryotes, including Mycobacterium tuberculosis. In spite of their general significance, their binding mechanism has not been studied in any detail. In particular, the molecular basis of their extraordinary and unique specificity for phosphothreonine has remained somewhat enigmatic.
In a recent study published in Structure, Steve Smerdon's lab in NIMR's Division of Molecular Structure, in collaboration with Roger Buxton in NIMR's Division on Mycobacterial Research, Mike Yaffe at MIT and Chandra Verma in Singapore, has now shown how this remarkable pThr-dependence is generated at the structural level.
We have been working on these domains pretty much since they were first discovered. We have solved quite a few structures of these things over the years in complex with various phospho-binding partners but have always wondered how and why they have 'chosen' phospho-threonine as their preferred interacting partner. The answer to 'why' probably relates to the observed ratio of phospho-serine and phospho-threonine in mammalian phosphoproteomes where pSer occurs 5-10 times more frequently than the relative abundance of the basic amino-acids (nearer 2:1) would suggest. FHA domains therefore are able to reduce the background noise of potential non-specific phosphoserine sites effectively to zero! Thanks to our latest work we now also know the answer to 'how', and that is immensely satisfying!
Steve Smerdon
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The structure of the bound phosphothreonine peptide shows how the extra methyl group, characteristic of threonine, restricts rotation of the side-chain and stabilises the pattern of hydrogen-bonds that provide the phospho-dependent 'switch'.
Original article
Simon Pennell, Sarah Westcott, Miguel Ortiz-Lombardía, Dony Patel, Jiejin Li, Timothy J. Nott, Duaa Mohammed, Roger S. Buxton, Michael B. Yaffe, Chandra Verma, Stephen J. Smerdon (2010)
Structural and functional analysis of phosphothreonine-dependent FHA domain interactions
Structure 18(12):1587-1595. Fulltext
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