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J. Biol. Chem., Vol. 280, Issue 12, 11535-11543, March 25, 2005

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Dissection of the Mitochondrial Import and Assembly Pathway for Human Tom40^*

Adam D. Humphries, Illo C. Streimann¶, Diana Stojanovski¶, Amelia J. Johnston, Masato Yano||, Nicholas J. Hoogenraad**, and Michael T. Ryan

From the Department of Biochemistry, La Trobe University, Melbourne 3086, Australia and the ^||Department of Molecular Genetics, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan

Tom40 is the channel-forming subunit of the translocase of the mitochondrial outer membrane (TOM complex), essential for protein import into mitochondria. Tom40 is synthesized in the cytosol and contains information for its mitochondrial targeting and assembly. A number of stable import intermediates have been identified for Tom40 precursors in fungi, the first being an association with the sorting and assembly machinery (SAM) of the outer membrane. By examining the import pathway of human Tom40, we have been able to elucidate additional features in its import. We identify that Hsp90 is involved in delivery of the Tom40 precursor to mitochondria in an ATP-dependent manner. The precursor then forms its first stable intermediate with the outer face of the TOM complex before its membrane integration and assembly. Deletion of an evolutionary conserved region within Tom40 disrupts the TOM complex intermediate and causes it to stall at a new complex in the intermembrane space that we identify to be the mammalian SAM. Unlike its fungal counterparts, the human Tom40 precursor is not found stably arrested at a SAM intermediate. Nevertheless, we show that Tom40 assembly is reduced in mitochondria depleted of human Sam50. These findings are discussed in context with current models from fungal studies.

Received for publication, December 8, 2004 , and in revised form, January 7, 2005.

^* This work was supported by grants from the Australian Research Council, National Health and Medical Research Council, and Wellcome Foundation. 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.

These authors contributed equally to this work.

^¶ Recipient of Australian postgraduate research awards.

^** To whom correspondence may be addressed. Tel.: 61-3-9479-2196; Fax: 61-3-9479-2467; E-mail: N.Hoogenraad{at}latrobe.edu.au. To whom correspondence may be addressed. Tel.: 61-3-9479-2156; Fax: 61-3-9479-2467; E-mail: M.Ryan{at}latrobe.edu.au.

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