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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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WRAP-Force-generation-KIF1C-impaired-pathogenic-mutations-22.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (25Mb) | Preview |
Official URL: http://dx.doi.org/10.1016/j.cub.2022.07.029
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 | |||||||||||||||
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| Subjects: | Q Science > QH Natural history > QH301 Biology Q Science > QP Physiology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| 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: |
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| 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: |
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