Journal article
A neuropathy-associated kinesin KIF1A mutation hyper-stabilizes the motor-neck interaction during the ATPase cycle
The EMBO journal, Vol.41(5), pp.e108899-e108899
02/08/2022
DOI: 10.15252/embj.2021108899
PMCID: PMC8886545
PMID: 35132656
Abstract
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.
Details
- Title: Subtitle
- A neuropathy-associated kinesin KIF1A mutation hyper-stabilizes the motor-neck interaction during the ATPase cycle
- Creators
- Manatsu Morikawa - Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanNivedita U Jerath - Neuromuscular Division, AdventHealth Orlando, Winter Park, FL, USATadayuki Ogawa - Research Center for Advanced Medical Science, Dokkyo Medical University, Mibu, JapanMomo Morikawa - Department of Anatomy and Neuroscience, Faculty of Medicine, University of Tsukuba, Tsukuba, JapanYosuke Tanaka - Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanMichael E Shy - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA, USAStephan Zuchner - Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USANobutaka Hirokawa - Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Resource Type
- Journal article
- Publication Details
- The EMBO journal, Vol.41(5), pp.e108899-e108899
- DOI
- 10.15252/embj.2021108899
- PMID
- 35132656
- PMCID
- PMC8886545
- NLM abbreviation
- EMBO J
- eISSN
- 1460-2075
- Grant note
- U54NS065712 / The Office of Rare Diseases JP23000013 / MEXT|Japan Society for the Promotion of Science (JSPS) JP16H06372 / MEXT|Japan Society for the Promotion of Science (JSPS) JP20dm0107084 / Japan Agency for Medical Research and Development (AMED) HHS|NIH|National Institute of Neurological Disorders and Stroke (NINDS) The Charcot-Marie-Tooth Association Uehara Memorial Foundation () The Muscular Dystrophy Association JP20K16483 / MEXT|Japan Society for the Promotion of Science (JSPS)
- Language
- English
- Date published
- 02/08/2022
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984215030302771
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