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Vol. 16, Issue 3, 1406-1416, March 2005

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Organelle-specific Control of Intracellular Transport: Distinctly Targeted Isoforms of the Regulator Klar

Yi Guo ^* , Sushrut Jangi ^* , and Michael A. Welte ^* 

^* Rosenstiel Biomedical Research Center, Brandeis University, Waltham, MA 02454; Department of Biochemistry, Brandeis University, Waltham, MA 02454; and Department of Biology, Brandeis University, Waltham, MA 02454

Submitted October 22, 2004; Revised December 22, 2004; Accepted December 30, 2004
Monitoring Editor: Susan Strome

Microtubule-based transport in cells is powered by a small set of distinct motors, yet timing and destination of transport can be controlled in a cargo-specific manner. The mechanistic basis for this specificity is not understood. To address this question, we analyzed the Drosophila Klarsicht (Klar) protein that regulates distinct microtubule-based transport processes. We find that localization of Klar to its cargoes is crucial for Klar function. Using mutations, we identify functionally important regions of Klar that confer distinct cargo specificity. In ovaries, Klar is present on the nuclear envelope, a localization that requires the C-terminal KASH domain. In early embryos, Klar is attached to lipid droplets, a localization mediated by a novel C-terminal domain encoded by an alternatively spliced exon. In cultured cells, these two domains are sufficient for targeting to the correct intracellular location. Our analysis disentangles Klar's modular organization: we propose that a core region integral to motor regulation is attached to variable domains so that the cell can target regulators with overlapping, yet distinct functions to specific cargoes. Such isoform variation may be a general strategy for adapting a common regulatory mechanism to specifically control motion and positioning of multiple organelles.

Abbreviations used: BDGP, Berkeley Drosophila genome project; LD, lipid-droplet domain of Klar.

Address correspondence to: Michael A. Welte (welte{at}brandeis.edu).

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