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Lancaster, United Kingdom

Burgess S.G.,University of Leicester | Burgess S.G.,Cancer Research Leicester Center | Bayliss R.,University of Leicester | Bayliss R.,Cancer Research Leicester Center | Pfuhl M.,Kings College London
Biomolecular NMR Assignments | Year: 2015

TOG domains contribute to the organisation of microtubules through their ability to bind tubulin. They are found in members of the XMAP215 family of proteins, which act as microtubule polymerases and fulfill important roles in the formation of the mitotic spindle and in the assembly of kinetochore fibres. We recently identified a cryptic TOG domain in the XMAP215 family proteins, chTOG and its Drosophila homologue, mini spindles. This domain is not part of the well-established array of TOG domains involved in tubulin polymerisation. Instead it forms part of a binding site for TACC3 family proteins. This interaction is required for the assembly of kinetochore bridges in a trimeric complex with clathrin. Here we present the first NMR assignment of a sixth TOG domain from mini spindles as a first step to elucidate its structure and function. © 2015, Springer Science+Business Media Dordrecht. Source


Haq T.,University of Leicester | Haq T.,Cancer Research Leicester Center | Richards M.W.,University of Leicester | Richards M.W.,Cancer Research Leicester Center | And 13 more authors.
Nature Communications | Year: 2015

Mitotic spindle assembly requires the regulated activities of protein kinases such as Nek7 and Nek9. Nek7 is autoinhibited by the protrusion of Tyr97 into the active site and activated by the Nek9 non-catalytic C-terminal domain (CTD). CTD binding apparently releases autoinhibition because mutation of Tyr97 to phenylalanine increases Nek7 activity independently of Nek9. Here we find that self-association of the Nek9-CTD is needed for Nek7 activation. We map the minimal Nek7 binding region of Nek9 to residues 810-828. A crystal structure of Nek7 Y97F bound to Nek9 810-828 reveals a binding site on the C-lobe of the Nek7 kinase domain. Nek7 Y97F crystallizes as a back-to-back dimer between kinase domain N-lobes, in which the specific contacts within the interface are coupled to the conformation of residue 97. Hence, we propose that the Nek9-CTD activates Nek7 through promoting back-to-back dimerization that releases the autoinhibitory tyrosine residue, a mechanism conserved in unrelated kinase families. © 2015 Macmillan Publishers Limited. All rights reserved. Source

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