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Mechanistic basis of Nek7 activation through Nek9 binding and induced dimerization

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posted on 13.11.2015, 10:28 by Tamanna Haq, Mark W. Richards, Selena G. Burgess, Pablo Gallego, Sharon Yeoh, Laura O'Regan, David Reverter, Joan Roig, Andrew M. Fry, Richard Bayliss
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.

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Citation

Nature Communications, 2015, 6 : 8771

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Molecular & Cell Biology

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VoR (Version of Record)

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Nature Communications

Publisher

Nature Publishing Group

eissn

2041-1723

Acceptance date

01/10/2015

Copyright date

2015

Available date

13/11/2015

Publisher version

http://www.nature.com/ncomms/2015/151102/ncomms9771/full/ncomms9771.html

Language

en

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