The KIF3B/B/KAP3 tail domain specifically facilitates TRIM46 transport to the axon initial segment

Intracellular transport is essential for neuronal organization, yet how motor proteins achieve cargo selectivity remains incompletely understood. Kinesin-2 motors transport diverse cargos through the heterotrimeric KIF3/KAP3 complex, but whether variations in assembly composition contribute to functional specificity has been unclear. This study provides evidence for heterogeneity in neuronal KIF3/KAP3 assemblies, including a KIF3B-enriched, KAP3-associated population in addition to the canonical KIF3A/B/KAP3 complex. Biochemical and cellular analyses support a preferential association between this KIF3B-enriched assembly and TRIM46, a protein required for axon initial segment organization. Structural analyses further suggest that differences in tail conformation accompany distinct assembly states and may underlie cargo selectivity. Together, these findings support a model in which compositional and structural diversity within kinesin-2 complexes contributes to spatially regulated transport during neuronal development.