Intragenic suppressors of unc-104 ( e1265 ) identify potential roles of the conserved stalk region

UNC-104 and its mammalian ortholog, KIF1A, are microtubule motor proteins required for moving synaptic vesicle precursors from neuronal cell bodies to presynaptic sites. These motor proteins consist of N-terminal motor domain, followed by a neck region, three coiled-coil domains and a FHA domain, and a C-terminal PH domain. Between the coiled-coil 3 and the PH domain is a large uncharacterized region called stalk. In C. elegans unc-104 ( e1265 ), a partial loss of function mutant, synaptic vesicles are retained in the cell body and absent from presynaptic sites. unc-104 ( e1265 ) contains amino acid substitution D1497N in the PH domain and the mutant proteins show reduced PI(4,5)P(2) binding. Through genetic suppressor screening, we identified amino acid substitutions in a conserved region of the stalk that cause intragenic suppression of unc-104 ( e1265 ). Currently, little is known about the functions of the stalk region. Our findings imply potential compensatory or antagonistic interaction between the stalk region and the cargo binding PH domain.