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Mechanistic basis of Nek7 activation through Nek9 binding and induced dimerization

DOI: 10.1038/ncomms9771 DOI Help
PMID: 26522158 PMID Help

Authors: Tamanna Haq (University of Leicester) , Mark W. Richards (University of Leicester) , Selena G. Burgess (University of Leicester) , Pablo Gallego (Universitat Autònoma de Barcelona) , Sharon Yeoh (University of Leicester) , Laura O’regan (University of Leicester) , David Reverter (Universitat Autònoma de Barcelona) , Joan Roig (Institute for Research in Biomedicine) , Andrew M. Fry (University of Leicester) , Richard Bayliss (University of Leicester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 6

State: Published (Approved)
Published: November 2015
Diamond Proposal Number(s): 10369

Open Access Open Access

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.

Journal Keywords: Biological sciences

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography