Nott, T.J.; (2009) Structural and functional analysis of a phospho-dependent molecular switch: Rv1827 from Mycobacterium tuberculosis. Doctoral thesis, UCL (University College London).
|PDF - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader|
Forkhead-associated (FHA) domains have gained considerable prominence as ubiquitous phosphothreonine-dependent binding modules; however, their precise roles in Ser/Thr kinase pathways and mechanisms of regulation remain unclear. From experiments with Rv1827, an FHA domain–containing protein from Mycobacterium tuberculosis, a complete molecular description of an FHA-mediated Ser/Thr protein kinase signalling process is derived. First, binding of the FHA domain to each of three metabolic enzyme complexes regulates their catalytic activities but does not require priming phosphorylation. However, phosphorylation of a threonine residue within a conserved N-terminal motif of Rv1827 triggers its intramolecular association with the FHA domain of Rv1827, thus blocking its interactions with each of the three enzymes. The nuclear magnetic resonance structure of this inactivated form and further mutagenic studies show how a novel intramolecular phospho-switch blocks the access of the target enzymes to a common FHA interaction surface and how this shared surface accommodates three functionally related, but structurally diverse, binding partners. Thus a remarkable and unsuspected versatility in the FHA domain that allows for the transformation of multiple kinase inputs into various downstream regulatory signals has been revealed.
|Title:||Structural and functional analysis of a phospho-dependent molecular switch: Rv1827 from Mycobacterium tuberculosis|
|Open access status:||An open access version is available from UCL Discovery|
|Additional information:||This work was funded by the MRC National Institute for Medical Research|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Structural and Molecular Biology|
View download statistics for this item
Activity - last month
Activity - last 12 months
Archive Staff Only: edit this record