5de2

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Structural mechanism of Nek7 activation by Nek9-induced dimerisation

Structural highlights

5de2 is a 4 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.78Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NEK7_HUMAN Protein kinase which plays an important role in mitotic cell cycle progression. Required for microtubule nucleation activity of the centrosome, robust mitotic spindle formation and cytokinesis. Phosphorylates RPS6KB1.[1] [2] [3]

Publication Abstract from PubMed

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.

Mechanistic basis of Nek7 activation through Nek9 binding and induced dimerization.,Haq T, Richards MW, Burgess SG, Gallego P, Yeoh S, O'Regan L, Reverter D, Roig J, Fry AM, Bayliss R Nat Commun. 2015 Nov 2;6:8771. doi: 10.1038/ncomms9771. PMID:26522158[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Yissachar N, Salem H, Tennenbaum T, Motro B. Nek7 kinase is enriched at the centrosome, and is required for proper spindle assembly and mitotic progression. FEBS Lett. 2006 Nov 27;580(27):6489-95. Epub 2006 Nov 7. PMID:17101132 doi:http://dx.doi.org/10.1016/j.febslet.2006.10.069
  2. ↑ Kim S, Lee K, Rhee K. NEK7 is a centrosomal kinase critical for microtubule nucleation. Biochem Biophys Res Commun. 2007 Aug 17;360(1):56-62. Epub 2007 Jun 8. PMID:17586473 doi:http://dx.doi.org/10.1016/j.bbrc.2007.05.206
  3. ↑ O'Regan L, Fry AM. The Nek6 and Nek7 protein kinases are required for robust mitotic spindle formation and cytokinesis. Mol Cell Biol. 2009 Jul;29(14):3975-90. doi: 10.1128/MCB.01867-08. Epub 2009 May , 4. PMID:19414596 doi:http://dx.doi.org/10.1128/MCB.01867-08
  4. ↑ Haq T, Richards MW, Burgess SG, Gallego P, Yeoh S, O'Regan L, Reverter D, Roig J, Fry AM, Bayliss R. Mechanistic basis of Nek7 activation through Nek9 binding and induced dimerization. Nat Commun. 2015 Nov 2;6:8771. doi: 10.1038/ncomms9771. PMID:26522158 doi:http://dx.doi.org/10.1038/ncomms9771

Contents


PDB ID 5de2

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OCA

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