Mechanistic basis of Nek7 activation through Nek9 binding and induced dimerization

Tamanna Haq, Mark W. Richards, Selena G. Burgess, Pablo Gallego, Sharon Yeoh, Laura O’Regan, David Reverter, Joan Roig, Andrew M. Fry and Richard Bayliss ()
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Tamanna Haq: University of Leicester
Mark W. Richards: University of Leicester
Selena G. Burgess: University of Leicester
Pablo Gallego: Departament de Bioquimica i Biologia Molecular, Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona
Sharon Yeoh: University of Leicester
Laura O’Regan: University of Leicester
David Reverter: Departament de Bioquimica i Biologia Molecular, Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona
Joan Roig: Cell and Developmental Biology Program, Institute for Research in Biomedicine
Andrew M. Fry: University of Leicester
Richard Bayliss: University of Leicester

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract 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 Nek7Y97F bound to Nek9810–828 reveals a binding site on the C-lobe of the Nek7 kinase domain. Nek7Y97F 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.

Date: 2015
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DOI: 10.1038/ncomms9771

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