MBE Advance Access originally published online on February 28, 2007
Molecular Biology and Evolution 2007 24(5):1149-1160; doi:10.1093/molbev/msm031
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Research Articles |
Conserved Motifs Reveal Details of Ancestry and Structure in the Small TIM Chaperones of the Mitochondrial Intermembrane Space
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* Department of Biochemistry & Molecular Biology, University of Melbourne, Parkville, Victoria, Australia
Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria, Australia
Institute of Molecular Biology & Biotechnology, Foundation for Research & Technology Hellas, Heraklion, Crete, Greece
Department of Biology/Cell & Developmental Biology, University of Fribourg, Fribourg, Switzerland
|| Department of Materials Science and Technology, University of Crete, Heraklion, Crete, Greece
E-mail: t.lithgow{at}unimelb.edu.au; tokatlid{at}imbb.forth.gr.
Accepted for publication February 17, 2007.
The mitochondrial inner and outer membranes are composed of a variety of integral membrane proteins, assembled into the membranes posttranslationally. The small translocase of the inner mitochondrial membranes (TIMs) are a group of 
10 kDa proteins that function as chaperones to ferry the imported proteins across the mitochondrial intermembrane space to the outer and inner membranes. In yeast, there are 5 small TIM proteins: Tim8, Tim9, Tim10, Tim12, and Tim13, with equivalent proteins reported in humans. Using hidden Markov models, we find that many eukaryotes have proteins equivalent to the Tim8 and Tim13 and the Tim9 and Tim10 subunits. Some eukaryotes provide "snapshots" of evolution, with a single protein showing the features of both Tim8 and Tim13, suggesting that a single progenitor gene has given rise to each of the small TIMs through duplication and modification. We show that no "Tim12" family of proteins exist, but rather that variant forms of the cognate small TIMs have been recently duplicated and modified to provide new functions: the yeast Tim12 is a modified form of Tim10, whereas in humans and some protists variant forms of Tim9, Tim8, and Tim13 are found instead. Sequence motif analysis reveals acidic residues conserved in the Tim10 substrate-binding tentacles, whereas more hydrophobic residues are found in the equivalent substrate-binding region of Tim13. The substrate-binding region of Tim10 and Tim13 represent structurally independent domains: when the acidic domain from Tim10 is attached to Tim13, the Tim8–Tim1310 complex becomes essential and the Tim9–Tim10 complex becomes dispensable. The conserved features in the Tim10 and Tim13 subunits provide distinct binding surfaces to accommodate the broad range of substrate proteins delivered to the mitochondrial inner and outer membranes.
Key Words: mitochondria • protein import • hidden Markov model • protein translocase • molecular parasitology
1 Equal contribution to this work
Geoffrey McFadden, Associate Editor
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