The C66W mutation in the deafness dystonia peptide 1 (DDP1) affects the formation of functional DDP1.TIM13 complexes in the mitochondrial intermembrane space.
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 Cys(4) 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 Cys(4) 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 Zn(2+) ions via the Cys(4) 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.
Hofmann
Sabine
S
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, Germany.
Rothbauer
Uli
U
Mühlenbein
Nicole
N
Neupert
Walter
W
Gerbitz
Klaus-Dieter
KD
Brunner
Michael
M
Bauer
Matthias F
MF
D020816:Amino Acid Motifs; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D006801:Humans; D026901:Membrane Transport Proteins; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D009154:Mutation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011817:Rabbits; D029701:Saccharomyces cerevisiae Proteins; D015032:Zinc / Q000378:metabolism; D016335:Zinc Fingers
D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D011506:Proteins; D029701:Saccharomyces cerevisiae Proteins; C403093:TIM13 protein, S cerevisiae; C485737:TIMM13 protein, human; C118122:TIMM8A protein, human; D015032:Zinc