The divergent mitotic kinesin MKLP2 exhibits atypical structure and mechanochemistry

Joseph Atherton, I. Mei Yu, Alexander Cook, Joseph M. Muretta, Agnel Joseph, Jennifer Major, Yannick Sourigues, Jeffrey Clause, Maya Topf, Steven S. Rosenfeld, Anne Houdusse, Carolyn A. Moores

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

MKLP2, a kinesin-6, has critical roles during the metaphase-anaphase transition and cytokinesis. Its motor domain contains conserved nucleotide binding motifs, but is divergent in sequence (~35% identity) and size (~40% larger) compared to other kinesins. Using cryo-electron microscopy and biophysical assays, we have undertaken a mechanochemical dissection of the microtubule-bound MKLP2 motor domain during its ATPase cycle, and show that many facets of its mechanism are distinct from other kinesins. While the MKLP2 neck-linker is directed towards the microtubule plus-end in an ATP-like state, it does not fully dock along the motor domain. Furthermore, the footprint of the MKLP2 motor domain on the MT surface is altered compared to motile kinesins, and enhanced by kinesin-6-specific sequences. The conformation of the highly extended loop6 insertion characteristic of kinesin-6s is nucleotide-independent and does not contact the MT surface. Our results emphasize the role of family-specific insertions in modulating kinesin motor function.

Original languageEnglish (US)
Article numbere27793
JournaleLife
Volume6
DOIs
StatePublished - Aug 11 2017

Bibliographical note

Funding Information:
1Institute of Structural and Molecular Biology, Birkbeck College, London, United Kingdom; 2Structural Motility, Institut Curie, Centre National de la Recherche Scientifique, Unité Mixte de Recherche, Paris, France; 3Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United Sates; 4Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States

Funding Information:
JA, CAM (MR/J000973/1), AC (MR/J003867/1), A-PJ and MT (MR/M019292/1) are supported by the Medical Research Council, UK. JMM was supported by funding from the American Heart Association (SDG20480032). SRR is supported by funding from NIH (GM102875 and NS073610). AH was supported by grants from the CNRS, ANR-15-CE13-0017-01, Instruct-pilote, Ligue Contre le Cancer (RS14/75-28), ARC (PJA 20151203285) and INCa (2016–1-PL BIO-10-ICR-1). I-MY has been awarded a Marie Curie Fellowship FP7-PEOPLE-2012-IIF. The AH team is part of Labex CelTisPhyBio 11-LBX-0038, which is part of the Initiative d’Excellence at PSL Research University (ANR-10-IDEX-0001–02 PSL). The authors thank Charles Sindelar (Yale University, USA) for reconstruction algorithms.

Funding Information:
Medical Research Council

Funding Information:
Australian Research Council

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