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Central role of Tim17 in mitochondrial presequence protein translocation.

ABSTRACT: The presequence translocase of the mitochondrial inner membrane (TIM23) represents the major route for the import of nuclear-encoded proteins into mitochondria^1,2. About 60% of more than 1,000 different mitochondrial proteins are synthesized with amino-terminal targeting signals, termed presequences, which form positively charged amphiphilic α-helices^3,4. TIM23 sorts the presequence proteins into the inner membrane or matrix. Various views, including regulatory and coupling functions, have been reported on the essential TIM23 subunit Tim17 (refs. ^5-7). Here we mapped the interaction of Tim17 with matrix-targeted and inner membrane-sorted preproteins during translocation in the native membrane environment. We show that Tim17 contains conserved negative charges close to the intermembrane space side of the bilayer, which are essential to initiate presequence protein translocation along a distinct transmembrane cavity of Tim17 for both classes of preproteins. The amphiphilic character of mitochondrial presequences directly matches this Tim17-dependent translocation mechanism. This mechanism permits direct lateral release of transmembrane segments of inner membrane-sorted precursors into the inner membrane.

SUBMITTER: Fielden LF

PROVIDER: S-EPMC10511324 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Central role of Tim17 in mitochondrial presequence protein translocation.

Fielden Laura F LF Busch Jakob D JD Merkt Sandra G SG Ganesan Iniyan I Steiert Conny C Hasselblatt Hanna B HB Busto Jon V JV Wirth Christophe C Zufall Nicole N Jungbluth Sibylle S Noll Katja K Dung Julia M JM Butenko Ludmila L von der Malsburg Karina K Koch Hans-Georg HG Hunte Carola C van der Laan Martin M Wiedemann Nils N

Nature 20230801 7979

The presequence translocase of the mitochondrial inner membrane (TIM23) represents the major route for the import of nuclear-encoded proteins into mitochondria<sup>1,2</sup>. About 60% of more than 1,000 different mitochondrial proteins are synthesized with amino-terminal targeting signals, termed presequences, which form positively charged amphiphilic α-helices<sup>3,4</sup>. TIM23 sorts the presequence proteins into the inner membrane or matrix. Various views, including regulatory and coupling ...[more]

PMID: 37527780

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Project description:BackgroundThe Tim17 family of proteins plays a fundamental role in the biogenesis of mitochondria. Three Tim17 family proteins, Tim17, Tim22, and Tim23, are the central components of the widely conserved multi-subunit protein translocases, TIM23 and TIM22, which mediate protein transport across and into the inner mitochondrial membrane, respectively. In addition, several Tim17 family proteins occupy the inner and outer membranes of plastids.ResultsWe have performed comprehensive sequence analyses on 5631 proteomes from all domains of life deposited in the Uniprot database. The analyses showed that the Tim17 family of proteins is much more diverse than previously thought and involves at least ten functionally and phylogenetically distinct groups of proteins. As previously shown, mitochondrial inner membrane accommodates prototypical Tim17, Tim22 and Tim23 and two Tim17 proteins, TIMMDC1 and NDUFA11, which participate in the assembly of complex I of the respiratory chain. In addition, we have identified Romo1/Mgr2 as Tim17 family member. The protein has been shown to control lateral release of substrates fromTIM23 complex in yeast and to participate in the production of reactive oxygen species in mammalian cells. Two peroxisomal proteins, Pmp24 and Tmem135, of so far unknown function also belong to Tim17 protein family. Additionally, a new group of Tim17 family proteins carrying a C-terminal coiled-coil domain has been identified predominantly in fungi.ConclusionsWe have mapped the distribution of Tim17 family members in the eukaryotic supergroups and found that the mitochondrial Tim17, Tim22 and Tim23 proteins, as well as the peroxisomal Tim17 family proteins, were all likely to be present in the last eukaryotic common ancestor (LECA). Thus, kinetoplastid mitochondria previously identified as carrying a single Tim17protein family homologue are likely to be the outcome of a secondary reduction. The eukaryotic cell has modified mitochondrial Tim17 family proteins to mediate different functions in multiple cellular compartments including mitochondria, plastids and peroxisomes. Concerning the origin of Tim17 protein family, our analyses do not support the affiliation of the protein family and the component of bacterial amino acid permease. Thus, it is likely that Tim17 protein family is exclusive to eukaryotes.ReviewersThe article was reviewed by Michael Gray, Martijn Huynen and Kira Makarova.

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Central role of Tim17 in mitochondrial presequence protein translocation.

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Central role of Tim17 in mitochondrial presequence protein translocation.

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