1. Motor domain-mediated autoinhibition dictates axonal transport by the kinesin UNC-104/KIF1A
- Author
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Yurong Zhou, Dezi Cong, Mei Ding, Wei Feng, Jingjing Liang, Jinqi Ren, and Shuang Wang
- 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 - 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., 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.
- Published
- 2021