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Vol. 15, Issue 8, 3729-3739, August 2004

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The Lipid Binding Pleckstrin Homology Domain in UNC-104 Kinesin is Necessary for Synaptic Vesicle Transport in Caenorhabditis elegans

Dieter R. Klopfenstein ^* , and Ronald D. Vale ^*  

^* Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94143; The Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143

Submitted April 21, 2004; Revised May 12, 2004; Accepted May 13, 2004
Monitoring Editor: Lawrence Goldstein

UNC-104 (KIF1A) is a kinesin motor that transports synaptic vesicles from the neuronal cell body to the terminal. Previous in vitro studies have shown that a Dictyostelium relative of UNC-104 transports liposomes containing acidic phospholipids, but whether this interaction is needed for the recognition and transport of synaptic vesicles in metazoans remains unexplored. Here, we have introduced mutations in the nonmotor domain of UNC-104 and examined whether these mutant motors can rescue an unc-104 Caenorhabditis elegans strain. We show that a pleckstrin homology (PH) domain in UNC-104 is essential for membrane transport in living C. elegans, that this PH domain binds specifically to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P₂), and that point mutants in the PH domain that interfere with PI(4,5)P₂ binding in vitro also interfere with UNC-104 function in vivo. Several other lipid-binding modules could not effectively substitute for the UNC-104 PH domain in this in vivo assay. Real time imaging also revealed that a lipid-binding point mutation in the PH domain reduced movement velocity and processivity of individual UNC-104::GFP punctae in neurites. These results reveal a critical role for PI(4,5)P₂ binding in UNC-104–mediated axonal transport and shows that the cargo-binding properties of the distal PH domain can affect motor output.

Abbreviations used: PI(4,5)P₂, phosphatidylinositol-4,5-bisphosphate.

Online version of this article contains supporting material. Online version is available at www.molbiolcell.org.

Present address: DFG Research Center for Molecular Physiology of the Brain, Georg August University, Humboldtallee 23, 37073 Göttingen, Germany.

Corresponding author. E-mail address: vale{at}cmp.ucsf.edu.

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