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J. Biol. Chem., Vol. 281, Issue 24, 16599-16606, June 16, 2006

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Domain Interactions within Fzo1 Oligomers Are Essential for Mitochondrial Fusion^*

From the Division of Biology, California Institute of Technology, Pasadena, California 91125

Mitofusins are conserved GTPases essential for the fusion of mitochondria. These mitochondrial outer membrane proteins contain a GTPase domain and two or three regions with hydrophobic heptad repeats, but little is known about how these domains interact to mediate mitochondrial fusion. To address this issue, we have analyzed the yeast mitofusin Fzo1p and find that mutation of any of the three heptad repeat regions (HRN, HR1, and HR2) leads to a null allele. Specific pairs of null alleles show robust complementation, indicating that functional domains need not exist on the same molecule. Biochemical analysis indicates that this complementation is due to Fzo1p oligomerization mediated by multiple domain interactions. Moreover, we find that two non-overlapping protein fragments, one consisting of HRN/GTPase and the other consisting of HR1/HR2, can form a complex that reconstitutes Fzo1p fusion activity. Each of the null alleles disrupts the interaction of these two fragments, suggesting that we have identified a key interaction involving the GTPase domain and heptad repeats essential for fusion.

Received for publication, February 27, 2006 , and in revised form, April 12, 2006.

^* This work was supported in part by National Institutes of Health Grant GM62967 (to D. C. C.). 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.

¹ A Beckman Young Investigator and Bren Scholar. To whom correspondence should be addressed: Div. of Biology, California Institute of Technology, 1200 E. California Blvd., MC114-96, Pasadena, CA 91125. Tel.: 626-395-2670; Fax: 626-395-8826; E-mail: dchan{at}caltech.edu.

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