Motor domain-mediated autoinhibition dictates axonal transport by the kinesin UNC-104/KIF1A.

Wei Feng,Jinqi Ren,Anne C. Hart,Yurong Zhou,Jingjing Liang,Shuang Wang,Mei Ding,Dezi Cong

doi:10.1371/journal.pgen.1009940

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.

Highlights

Neurons are highly specialized for the processing and transmission of cellular signals
Most kinesin-3 motors adopt an autoinhibited conformation, and how the UNC104/KIF1A motor is activated in vivo is not fully understood
In addition to the CC2-FHA and NC-CC1 interactions, we revealed that the intramolecular interaction between the motor domain and the CC1 domain is important for the autoinhibition of UNC-104/KIF1A motor

Summary

Introduction

Neurons are highly specialized for the processing and transmission of cellular signals. UNC-104/KIF1A was originally identified through genetic screens in C. elegans and is the primary kinesin motor for anterograde axonal transport of synaptic vesicle precursors [1,2,3]. KIF1A-mediated axonal transport of brain-derived neurotrophic factor (BDNF) and the TrkA neurotrophin receptor is essential for hippocampal synaptogenesis and sensory neuron survival [4,5]. KIF1A participates in controlling interkinetic nuclear migration in neural stem cells for brain development [6]. Given the aforementioned roles of KIF1A in neuronal development and synaptogenesis, it is unsurprising that mutations in the gene encoding this motor directly link with human neuronal disorders such as hereditary spastic paraparesis [7,8,9]

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Discussion

Conclusion