Intragenic Suppressors of ( ) 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 ( ), a partial loss of function mutant, synaptic vesicles are retained in the cell body and absent from presynaptic sites. ( ) 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 ( ). 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.