Nucleotide-free structures of KIF20A illuminate atypical mechanochemistry in this kinesin-6.

Autor: Ranaivoson FM; Structural Motility, CNRS UMR144, Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, 75248 Paris, France., Crozet V; Structural Motility, CNRS UMR144, Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, 75248 Paris, France., Benoit MPMH; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Abdalla Mohammed Khalid A; Third Institute of Physics-Biophysics, Georg August University Göttingen, 37077 Göttingen, Germany., Kikuti C; Structural Motility, CNRS UMR144, Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, 75248 Paris, France., Sirkia H; Structural Motility, CNRS UMR144, Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, 75248 Paris, France., El Marjou A; Structural Motility, CNRS UMR144, Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, 75248 Paris, France., Miserey-Lenkei S; Structural Motility, CNRS UMR144, Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, 75248 Paris, France., Asenjo AB; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Sosa H; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Schmidt CF; Third Institute of Physics-Biophysics, Georg August University Göttingen, 37077 Göttingen, Germany.; Department of Physics and Soft Matter Center, Duke University, Durham, NC 27708, USA., Rosenfeld SS; Department of Pharmacology, Mayo Clinic, Jacksonville, FL 32224, USA., Houdusse A; Structural Motility, CNRS UMR144, Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, 75248 Paris, France.
Jazyk: angličtina
Zdroj: Open biology [Open Biol] 2023 Sep; Vol. 13 (9), pp. 230122. Date of Electronic Publication: 2023 Sep 20.
DOI: 10.1098/rsob.230122
Abstrakt: 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-electron microscopy microtubule-bound KIF20A structure that reveals the microtubule-binding interface, we dissect the peculiarities of the KIF20A sequence that influence its mechanochemistry, leading to low motility compared to other kinesins. Structural and functional insights from the KIF20A pre-power stroke conformation highlight the role of extended insertions in shaping the motor's 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 four times longer than that in kinesin-1 is required for the activity of this motor.
Databáze: MEDLINE
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