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Force generation of KIF1C is impaired by pathogenic mutations

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Siddiqui, Nida, Roth, Daniel, Toleikis, Algirdas, Zwetsloot, Alexander J., Cross, Robert A. and Straube, Anne (2022) Force generation of KIF1C is impaired by pathogenic mutations. Cell Press.

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Official URL: http://dx.doi.org/10.1016/j.cub.2022.07.029

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Abstract

Intracellular transport is essential for neuronal function and survival. The most effective plus-end-directed neuronal transporter is the kinesin-3 KIF1C, which transports large secretory vesicles and endosomes.1, 2, 3, 4 Mutations in KIF1C cause hereditary spastic paraplegia and cerebellar dysfunction in human patients.5, 6, 7, 8 In contrast to other kinesin-3s, KIF1C is a stable dimer and a highly processive motor in its native state.9,10 Here, we establish a baseline for the single-molecule mechanics of Kif1C. We show that full-length KIF1C molecules can processively step against the load of an optical trap and reach average stall forces of 3.7 pN. Compared with kinesin-1, KIF1C has a higher propensity to slip backward under load, which results in a lower maximal single-molecule force. However, KIF1C remains attached to the microtubule while slipping backward and re-engages quickly, consistent with its super processivity. Two pathogenic mutations, P176L and R169W, that cause hereditary spastic paraplegia in humans7,8 maintain fast, processive single-molecule motility in vitro but with decreased run length and slightly increased unloaded velocity compared with the wild-type motor. Under load in an optical trap, force generation by these mutants is severely reduced. In cells, the same mutants are impaired in producing sufficient force to efficiently relocate organelles. Our results show how its mechanics supports KIF1C’s role as an intracellular transporter and explain how pathogenic mutations at the microtubule-binding interface of KIF1C impair the cellular function of these long-distance transporters and result in neuronal disease.

Item Type: Report
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QP Physiology
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Kinesin, Biological transport, Muscle proteins, Microtubules
Journal or Publication Title: Current Biology
Publisher: Cell Press
ISSN: 0960-9822
Official Date: 12 September 2022
Dates:
DateEvent
12 September 2022Published
11 August 2022Available
13 July 2022Accepted
Volume: 32
Number of Pages: 9
DOI: 10.1016/j.cub.2022.07.029
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 18 August 2022
Date of first compliant Open Access: 18 August 2022
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
200870/Z/16/Z Wellcome Trusthttp://dx.doi.org/10.13039/100010269
UNSPECIFIEDLister Institute of Preventive Medicinehttp://dx.doi.org/10.13039/501100001255
MR/N014294/1[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
103895/Z/14/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269

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