A neuropathy-associated kinesin KIF1A mutation hyper-stabilizes the motor-neck interaction during the ATPase cycle.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8208664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2075 (Electronic) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE

Publication: 2024- : [London] : Nature Publishing Group
Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982-

Adenosine Triphosphatases/*genetics ; Kinesins/*genetics ; Mutation/*genetics ; Neurons/*physiology; Aged ; Amino Acid Sequence ; Axons/physiology ; Charcot-Marie-Tooth Disease ; Humans ; Male ; Microtubules/genetics ; Middle Aged ; Sequence Alignment

The mechanochemical coupling of ATPase hydrolysis and conformational dynamics in kinesin motors facilitates intramolecular interaction cycles between the kinesin motor and neck domains, which are essential for microtubule-based motility. Here, we characterized a charge-inverting KIF1A-E239K mutant that we identified in a family with axonal-type Charcot-Marie-Tooth disease and also in 24 cases in human neuropathies including spastic paraplegia and hereditary sensory and autonomic neuropathy. We show that Glu239 in the β7 strand is a key residue of the motor domain that regulates the motor-neck interaction. Expression of the KIF1A-E239K mutation has decreased ability to complement Kif1a ^+/- neurons, and significantly decreases ATPase activity and microtubule gliding velocity. X-ray crystallography shows that this mutation causes an excess positive charge on β7, which may electrostatically interact with a negative charge on the neck. Quantitative mass spectrometric analysis supports that the mutation hyper-stabilizes the motor-neck interaction at the late ATP hydrolysis stage. Thus, the negative charge of Glu239 dynamically regulates the kinesin motor-neck interaction, promoting release of the neck from the motor domain upon ATP hydrolysis.
(© 2022 The Authors.)

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U54 NS065712 United States NS NINDS NIH HHS

Keywords: KIF1A; axonal transport; human neuropathies; motor-neck interaction; neuropathy-related mutation

RefSeq 7EOB; 7EO9; JPST001177; PXD026083

0 (KIF1A protein, human)
EC 3.6.1.- (Adenosine Triphosphatases)
EC 3.6.4.4 (Kinesins)

Date Created: 20220208 Date Completed: 20220308 Latest Revision: 20230302

20250114

PMC8886545

10.15252/embj.2021108899

35132656