Mechanistic basis of Nek7 activation through Nek9 binding and induced dimerization
Haq, Tamanna (University of Leicester. Department of Biochemistry)
Richards, Mark W. (University of Leicester. Department of Biochemistry)
Burgess, Selena G. (University of Leicester. Department of Biochemistry)
Gallego Alonso, Pablo (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Yeoh, Sharon (University of Leicester. Department of Biochemistry)
O'Regan, Laura (University of Leicester. Department of Biochemistry)
Reverter i Cendrós, David (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Roig, Joan (Institut de Recerca Biomèdica de Lleida)
Fry, Andrew M. (University of Leicester. Department of Biochemistry)
Bayliss, Richard (Cancer Research UK Leicester Centre)

Fecha:	2015
Resumen:	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.
Ayudas:	Ministerio de Economía y Competitividad BFU2012-37116 Ministerio de Economía y Competitividad BFU2011-25855
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Amino acid motifs ; Binding sites ; Catalytic domain ; Crystallography, X-Ray ; Dimerization ; HeLa cells ; Humans ; NIMA-related kinases ; Phosphorylation ; Protein binding ; Protein-serine-threonine kinases
Publicado en:	Nature communications, Vol. 6 (2015) , art. 8771, ISSN 2041-1723

DOI: 10.1038/ncomms9771
PMID: 26522158

12 p, 1.7 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Instituto de Biotecnología y de Biomedicina (IBB)
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