Back to Search
Start Over
Motor domain-mediated autoinhibition dictates axonal transport by the kinesin UNC-104/KIF1A
- Source :
- PLoS Genetics, Vol 17, Iss 11, p e1009940 (2021), PLoS Genetics
- Publication Year :
- 2021
- Publisher :
- Public Library of Science (PLoS), 2021.
-
Abstract
- The UNC-104/KIF1A motor is crucial for axonal transport of synaptic vesicles, but how the UNC-104/KIF1A motor is activated in vivo is not fully understood. Here, we identified point mutations located in the motor domain or the inhibitory CC1 domain, which resulted in gain-of-function alleles of unc-104 that exhibit hyperactive axonal transport and abnormal accumulation of synaptic vesicles. In contrast to the cell body localization of wild type motor, the mutant motors accumulate on neuronal processes. Once on the neuronal process, the mutant motors display dynamic movement similarly to wild type motors. The gain-of-function mutation on the motor domain leads to an active dimeric conformation, releasing the inhibitory CC1 region from the motor domain. Genetically engineered mutations in the motor domain or CC1 of UNC-104, which disrupt the autoinhibitory interface, also led to the gain of function and hyperactivation of axonal transport. Thus, the CC1/motor domain-mediated autoinhibition is crucial for UNC-104/KIF1A-mediated axonal transport in vivo.<br />Author summary UNC-104/KIF1A is the founding member of the kinesin-3 family. When not transporting cargos, most kinesin-3 motors adopt an autoinhibited conformation, and how the UNC-104/KIF1A motor is activated in vivo is not fully understood. Here, we identified gain-of-function mutations in the motor domain or CC1 domain that significantly enhance the synaptic vesicle transport. Further biochemical and structural analyses revealed that these mutations could disrupt the CC1/motor mediated autoinhibition. Thus, our work provides a mechanistic explanation for the role of some disease-related mutations in motor hyperactivation.
- Subjects :
- Adenosine Triphosphatase
Cancer Research
Physiology
Mutant
Kinesins
QH426-470
medicine.disease_cause
Nervous System
Axonal Transport
Biochemistry
Animal Cells
Medicine and Health Sciences
Genetics (clinical)
KIF1A
Neurons
Motor Neurons
Mutation
Enzymes
Cell biology
Electrophysiology
Cell Processes
Gain of Function Mutation
Kinesin
Synaptic Vesicles
Anatomy
Cellular Structures and Organelles
Cellular Types
Genetic Engineering
Research Article
Motor Proteins
Neurophysiology
Nerve Tissue Proteins
Biology
Inhibitory postsynaptic potential
Synaptic vesicle
Protein Domains
Molecular Motors
medicine
Genetics
Point Mutation
Animals
Vesicles
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Molecular Biology
Ecology, Evolution, Behavior and Systematics
Phosphatases
Wild type
Biology and Life Sciences
Proteins
Cell Biology
Neuronal Dendrites
nervous system
Cellular Neuroscience
Synapses
Enzymology
Axoplasmic transport
Neuroscience
Subjects
Details
- Language :
- English
- ISSN :
- 15537404 and 15537390
- Volume :
- 17
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.doi.dedup.....f350ed3fa45da84f38e49c2c47853c70