Role of KIF1 family kinesin motors in the formation of neuronal synapses

Abstract

The formation of neuronal synapses involves various molecular mechanisms including the transport of synaptic proteins, the synaptic assembly of these proteins, and adhesion of pre- and postsynaptic sites. Liprin-α/SYD-2 is a multimodular scaffolding protein important for presynaptic differentiation and postsynaptic targeting of alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) glutamate receptors. Liprin-α interacts with the neuron-specific kinesin motor KIF1A. KIF1A colocalizes with liprin-α in various subcellular regions of neurons. KIF1A coaccumulates with liprin-α in ligated sciatic nerves. KIF1A cofractionates and coimmunopreciptates with liprin-α and various liprin-α-associated membrane, signaling, and scaffolding proteins including AMPA receptors, GRIP/ABP, RIM, GIT1, and beta PIX. These results suggest that KIF1A functions as a neuronal motor protein transporting liprin-a and various liprin-α-associated proteins to their proper synaptic targets. KIF1Bα, one of the two splice variants of KIF1B, directly interacts through its C-terminal postsynaptic density-95 (PSD-95)/discs large/zona occludens (PDZ) domain-binding motif with PDZ proteins including PSD-95, SAP97, and synaptic scaffolding molecule (S-SCAM). KIF1Bα selectively interacts with PSD-95, SAP97, and S-SCAM in yeast two-hybrid, pull-down, and in vivo coimmunoprecipitation experiments. KIF1Bα, SAP97, and S-SCAM are widely distributed to both dendrites and axons of cultured neurons and are enriched in the small membrane fraction of the brain. In the flotation assay, KIF1Ba cofractionates and coimmunoprecipitates with PSD-95, SAP97, and S-SCAM. These results suggest that KIF1Bα transports synaptic molecules to their specific site by using PSD-95 family proteins and S-SCAM as receptors. In addition, KIF1Ba can be phosphorylated at its c-terminus in vivo and in vitro. A KIF1Ba mutant mimicking the phosphorylation of its c-terminus cannot interact with the cargos. In addition, A KIF1Ba m...