Abstract
AbstractAxonal transport is essential for cargo movement between the neuronal cell body and synapses. UNC-104/KIF1A, a Kinesin-3 motor inC. elegansthat anterogradely transports precursors of synaptic vesicles (pre-SVs), is known to be degraded at synapses through the ubiquitin pathway. Knockdown of the E1 ubiquitin-activating enzyme,uba-1, leads to increased accumulation of UNC-104 at neuronal ends and at synapses of touch receptor neurons (TRNs). Loss of the F-box protein FBXB-65, a putative E3 ligase, leads to UNC-104 accumulation at distal ends of neurons, alters net anterograde movement of UNC-104, and the intensity of moving UNC-104 puncta likely bound to cargo without changes in synaptic UNC-104 levels. Using a theoretical model, we analyze the steady state distribution of the anterogradely moving UNC-104 motor. A good agreement between the model and the experimental distributions leads to a crucial hypothesis that UNC-104 may exhibit cooperative binding with moving motor puncta likely associated with cargo, which is regulated byfbxb-65. FBXB-65 regulates the modification of UNC-104 motor in a region besides the cargo binding PH-domain. Bothfbxb-65and UNC-104 motor independent of FBXB-65 regulate the extent of cargo transport in the axon and transport behaviour of cargo at branch points. Our study shows that modification of UNC-104 near its cargo-binding domain may regulate number of motors on the cargo surface and this regulation can fine-tune cargo transport to its destination, the synapse.
Publisher
Cold Spring Harbor Laboratory
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