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J. Biol. Chem., Vol. 277, Issue 24, 21221-21230, June 14, 2002

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Species-specific and Mutant MWFE Proteins
THEIR EFFECT ON THE ASSEMBLY OF A FUNCTIONAL MAMMALIAN MITOCHONDRIAL COMPLEX I^*

Nagendra Yadava, Prasanth Potluri, Erin N. Smith, Amina Bisevac, and Immo E. Scheffler

From the Division of Biology and Center for Molecular Genetics, University of California, San Diego, La Jolla, California 92093-0322

The MWFE protein (70 amino acids) is highly conserved in evolution, but the human protein (80% identical to hamster) does not complement a null mutation in Chinese hamster cells. We have identified a small protein segment where significant differences exist between rodents and primates, illustrating very specifically the need for compatibility of the nuclear and mitochondrial genomes in the assembly of complex I. The segment between amino acids 39 and 46 appears to be critical for species-specific compatibility. Amino acid substitutions in this region were tested that caused a reduction of activity of the hamster protein or converted the inactive human protein into a partially active one. Such mutations could be useful in making mice with partial complex I activity as models for mitochondrial diseases. Their potential as dominant negative mutants was explored. More deleterious mutations in the NDUFA1 gene were also characterized. A conservative substitution, R50K, or a short C-terminal deletion makes the protein completely inactive. In the absence of MWFE, no high molecular weight complex was detectable by Blue Native-gel electrophoresis. The MWFE protein itself is unstable in the absence of assembled mitochondrially encoded integral membrane proteins of complex I.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF495658, AF495659, and AF495660.

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