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A more recent version of this article appeared on May 1, 2002
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Submitted on December 4, 2001
Revised on January 11, 2002
Accepted on January 28, 2002
1 Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
* Corresponding author. E-mail address: mihara{at}cell.med.kyushu-u.ac.jp.
We analyzed the signal that directs the outer membrane protein with the C-terminal transmembrane segment (TMS) to mammalian mitochondria using yeast Tom5 as a model and green fluorescent protein (GFP) as a reporter. Deletions or mutations were systematically introduced into the TMS or the flanking regions and their intracellular localization in COS-7 cells was examined using confocal microscopy and cell fractionation. (i) Three basic amino acid residues within the C-terminal five-residue segment (C-segment) contained the information required for mitochondrial-targeting. Reduction of the net positive charge in this segment decreased mitochondrial-specificity and the mutants were distributed throughout the intracellular membranes. (ii) Elongation of the TMS interfered with the function of the C-segment and the mutants were delivered to the intracellular membranes. (iii) Separation of the TMS and C-segment by linker insertion severely impaired mitochondrial-targeting function, leading to mislocalization to the cytoplasm. (iv) Mutations or small deletions in the region of the TMS flanking the C-segment also impaired the mitochondrial-targeting. Therefore, the moderate length of the TMS, the positive charges in the C-segment, and the distance between or context of the TMS and C-segment are critical for the targeting signal. The structural characteristics of the signal thus defined were also confirmed with mammalian C-tail anchored protein OMP25.
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