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J. Biol. Chem., Vol. 277, Issue 26, 23287-23293, June 28, 2002
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From the § Institut für Klinische Chemie,
Molekulare Diagnostik und Mitochondriale Genetik, Institut für
Diabetesforschung und Metabolic Disease Center München-Schwabing,
Akademisches Lehrkrankenhaus München-Schwabing, Koelner Platz 1,
München 80804, the ¶ Institut für Physiologische
Chemie der Universität München, Butenandtstrasse 5,
München 81377, the Mohr-Tranebjaerg syndrome is a progressive,
neurodegenerative disorder caused by loss-of-function mutations in the
DDP1/TIMM8A gene. DDP1 belongs to a family of evolutionary
conserved proteins that are organized in hetero-oligomeric complexes in
the mitochondrial intermembrane space. They mediate the import and
insertion of hydrophobic membrane proteins into the mitochondrial inner
membrane. All of them share a conserved Cys4 metal binding
site proposed to be required for the formation of zinc fingers. So far,
the only missense mutation known to cause a full-blown clinical
phenotype is a C66W exchange directly affecting this Cys4
motif. Here, we show that the mutant human protein is efficiently
imported into mitochondria and sorted into the intermembrane space. In
contrast to wild-type DDP1, it does not complement the function of its yeast homologue Tim8. The C66W mutation impairs binding of
Zn2+ ions via the Cys4 motif. As a consequence,
the mutated DDP1 is incorrectly folded and loses its ability to
assemble into a hetero-hexameric 70-kDa complex with its cognate
partner protein human Tim13. Thus, an assembly defect of DDP1 is the
molecular basis of Mohr-Tranebjaerg syndrome in patients carrying the
C66W mutation.
The C66W Mutation in the Deafness Dystonia Peptide 1 (DDP1)
Affects the Formation of Functional DDP1·TIM13 Complexes in the
Mitochondrial Intermembrane Space*
§,§,
, and Biochemie-Zentrum der Universität
Heidelberg, Im Neuenheimer Feld 328, Heidelberg 69120, Germany
*
This work was supported by the Deutsche
Forschungsgemeinschaft (Ba1438/3 and 4 to M. F. B.) and (Ho2374/1-1
to S. H.) and by the Bundesministerium für Bildung und Forschung
(BMBF: 01KW9953-MITOP Project) and the Stiftung für
Pathobiochemie der Deutschen Gesellschaft für Klinische Chemie
(to M. F. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Both authors contributed equally to this work.
**
To whom correspondence should be addressed. Tel.: 48-89-3079-3125;
Fax: 49-89-3068-3911; E-mail: bauer@bio.med.uni-muenchen.de.
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