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J. Biol. Chem., Vol. 280, Issue 7, 5934-5944, February 18, 2005

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Differential Regulation of Endoplasmic Reticulum Structure through VAP-Nir Protein Interaction^*

Roy Amarilio, Sreekumar Ramachandran, Helena Sabanay, and Sima Lev, Sima Lev is an incumbent of the Helena Rubinstein Career Development Chair¶

From the Neurobiology Department and the EM unit, Weizmann Institute of Science, Rehovot 76100, Israel

The endoplasmic reticulum (ER) exhibits a characteristic tubular structure that is dynamically rearranged in response to specific physiological demands. However, the mechanisms by which the ER maintains its characteristic structure are largely unknown. Here we show that the integral ER-membrane protein VAP-B causes a striking rearrangement of the ER through interaction with the Nir2 and Nir3 proteins. We provide evidence that Nir (Nir1, Nir2, and Nir3)-VAP-B interactions are mediated through the conserved FFAT (two phenylalanines (FF) in acidic tract) motif present in Nir proteins. However, each interaction affects the structural integrity of the ER differently. Whereas the Nir2-VAP-B interaction induces the formation of stacked ER membrane arrays, the Nir3-VAP-B interaction leads to a gross remodeling of the ER and the bundling of thick microtubules along the altered ER membranes. In contrast, the Nir1-VAP-B interaction has no apparent effect on ER structure. We also show that the Nir2-VAP-B interaction attenuates protein export from the ER. These results demonstrate new mechanisms for the regulation of ER structure, all of which are mediated through interaction with an identical integral ER-membrane protein.

Received for publication, August 19, 2004 , and in revised form, November 15, 2004.

^* This work was supported by the Israel Science Foundation (Grant No. 1073/03), the Israel Cancer Research Foundation, and by the Harry and Jeanette Weinberg Fund for the Molecular Genetics of Cancer. 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: Dept. of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel. Tel.: 972-8-934-2126; Fax: 972-8-934-4131; E-mail: sima.lev{at}weizmann.ac.il.

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