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J. Biol. Chem., Vol. 279, Issue 18, 18270-18276, April 30, 2004

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Ca²+ and N-Ethylmaleimide-sensitive Factor Differentially Regulate Disassembly of SNARE Complexes on Early Endosomes^*

Qing Yan, Wei Sun, James A. McNew, Thomas A. Vida¶, and Andrew J. Bean||

From the Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, Texas 77030, the Department of Biochemistry and Cell Biology, Rice University, Houston, Texas 77005, and the ^¶Department of Microbiology And Molecular Genetics, University of Texas Medical School, Houston, Texas 77030

The endosome-associated protein Hrs inhibits the homotypic fusion of early endosomes. A helical region of Hrs containing a Q-SNARE motif mediates this effect as well as its endosomal membrane association via SNAP-25, an endosomal receptor for Hrs. Hrs inhibits formation of an early endosomal SNARE complex by displacing VAMP-2 from the complex, suggesting a mechanism by which Hrs inhibits early endosome fusion. We examined the regulation of endosomal SNARE complexes to probe how Hrs may function as a negative regulator. We show that although NSF dissociates the VAMP-2·SNAP-25·syntaxin 13 complex, it has no effect on the Hrs-containing complex. Whereas Ca²⁺ dissociates the Hrs-containing complex but not the VAMP-2-containing SNARE complex. This is the first demonstration of differential regulation of R/Q-SNARE and all Q-SNARE-containing SNARE complexes. Ca²⁺ also reverses the Hrs-induced inhibition of early endosome fusion in a tetanus toxin-sensitive manner and removes Hrs from early endosomal membranes. Moreover, Hrs inhibition of endosome fusion and its endosomal localization are sensitive to bafilomycin, implying a role for luminal Ca²⁺. Thus, Hrs may bind a SNARE protein on early endosomal membranes negatively regulating trans-SNARE pairing and endosomal fusion. The release of Ca²⁺ from the endosome lumen dissociates Hrs, allowing a VAMP-2-containing complex to form enabling fusion.

Received for publication, January 6, 2004 , and in revised form, January 28, 2004.

^* This work was supported in part by National Institutes of Health Grant MH58920. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: UTHSC Dept. NBA, 6431 Fannin St. MSB 7.208, Houston, TX 77030. Tel.: 713-500-5614; E-mail: a.bean{at}uth.tmc.edu.

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