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Pré-Publication, Document De Travail Année : 2022

Nucleotide-free structures of Kif20A illuminate the atypical allostery in this mitotic kinesin-6

Fanomezana Moutse Ranaivoson
Vincent Crozet
  • Fonction : Auteur
Matthieu P.M.H. Benoît
Amna Abdalla Mohammed Khalid
  • Fonction : Auteur
Carlos Kikuti
Ahmed El Marjou
Ana Asenjo
Hernando Sosa
Christoph Schmidt
Steven Rosenfeld
Anne Houdusse
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Résumé

Abstract KIF20A is a critical kinesin for cell division and a promising anti-cancer drug target. The mechanisms underlying its cellular roles remain elusive. Interestingly, unusual coupling between the nucleotide- and microtubule-binding sites of this kinesin-6 has been reported but little is known about how its divergent sequence leads to atypical motility properties. We present here the first high-resolution structure of its motor domain that delineates the highly unusual structural features of this motor, including a long L6 insertion that integrates into the core of the motor domain and that drastically affects allostery and ATPase activity. Together with the high-resolution cryo-EM microtubule-bound KIF20A structure that reveal the microtubule-binding interface, we dissect the peculiarities of the KIF20A sequence that work to favor fast dissociation of ADP, particularly in contrast to other kinesins. Structural and functional insights from the KIF20A pre-power stroke conformation thus highlight the role of extended insertions in shaping the motor mechanochemical cycle. Essential for force production and processivity is the length of the neck linker in kinesins. We highlight here the role of the sequence preceding the neck linker in controlling its backward docking and show that a neck linker 4-times longer than kinesin-1 is required for the activity of this motor.
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Dates et versions

hal-03872652 , version 1 (25-11-2022)

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Fanomezana Moutse Ranaivoson, Vincent Crozet, Matthieu P.M.H. Benoît, Amna Abdalla Mohammed Khalid, Carlos Kikuti, et al.. Nucleotide-free structures of Kif20A illuminate the atypical allostery in this mitotic kinesin-6. 2022. ⟨hal-03872652⟩
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