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Translocase of the inner membrane

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Tim17/Tim22/Tim23 family
Identifiers
SymbolTim17
PfamPF02466
InterProIPR003397
TCDB3.A.8
OPM superfamily266
OPM protein3awr
Membranome169
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

The translocase of the inner membrane (TIM) is a complex of proteins found in the inner membrane of the mitochondrion. Components of the TIM complex facilitate the translocation of proteins across the inner membrane and into the mitochondrial matrix. They also facilitate the insertion of proteins into the inner mitochondrial membrane, where they must reside in order to function, these mainly include members of the mitochondrial carrier family of proteins.

The TIM23 complex

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The TIM23 complex facilitates translocation of matrix-targeted proteins into the mitochondrial matrix.[1] These proteins contain a cleavable presequence. The TIM23 complex is made up of the subunits Tim17, Tim21 and Tim23, which are thought to contribute to the structural formation of the translocation channel that spans the inner membrane, and Tim44, which is a peripheral membrane protein.[2] Tim44 is only weakly associated with Tim23 and is located on the matrix side of the inner membrane. At the opening of the TIM17-23 complex, Tim44 recruits mitochondrial heat shock protein 70, which further mediates translocation of the precursor through ATP hydrolysis.[3] Following protein entry into the matrix, the presequence is cleaved off by the matrix processing peptidase and the protein undergoes folding into an active conformation,[4] facilitated by HSP60.

The TIM22 complex

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The TIM22 complex is responsible for mediating the integration of carrier preproteins into the inner membrane. Tim22, a subunit of the TIM22 complex, forms a channel within the inner membrane and is referred to as the carrier translocase. Tim54 and the small Tim proteins, Tim9, Tim10 and Tim12 also contribute to the TIM22 complex[5] as well as Tim18. The function of Tim18 is not yet clear; however it is believed to play a role in assembly and stabilisation of the TIM22 complex, although is not involved in protein insertion into the membrane. Tim54, although it does not associate directly with Tim22, is also believed to assist in the stability of Tim22.[6] Unlike cleavable preproteins, following translocation across the outer membrane via the translocase of the outer membrane, carrier preproteins are bound by the soluble Tim9-Tim10 complex of which the majority of this complex (~95%) is free floating within the intermembrane space.[7] It is possible that this small Tim complex is able to stabilise precursor carrier proteins by acting as a chaperone and preventing the hydrophobic precursors from aggregating in the aqueous environment of the intermembrane space.[8] A small portion of Tim9 and Tim10 (~5%) assembles into a modified complex containing Tim12, on the outer surface of the TIM22 complex.[9] Tim12 is membrane bound and thus may act as a linker molecule docking Tim9 and Tim10 to the face of the TIM22 complex.[7] The carrier preprotein is then inserted into the inner mitochondrial membrane in a potential-dependent fashion.[10] The membrane potential is necessary for both insertion of the precursor into the carrier translocase and lateral release of the protein into the lipid phase of the inner mitochondrial membrane, which completes protein translocation. However this membrane potential-dependent process takes place in absence of ATP-driven machinery.[8]

Subfamilies

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Human proteins containing this domain

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TIM17A; TIMM17A; TIMM17B; TIMM22; TIMM23;

See also

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References

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  1. ^ Sirrenberg C, Bauer MF, Guiard B, Neupert W, Brunner M (December 1996). "Import of carrier proteins into the mitochondrial inner membrane mediated by Tim22". Nature. 384 (6609): 582–5. Bibcode:1996Natur.384..582S. doi:10.1038/384582a0. PMID 8955274.
  2. ^ Dekker PJ, Martin F, Maarse AC, Bömer U, Müller H, Guiard B, Meijer M, Rassow J, Pfanner N (September 1997). "The Tim core complex defines the number of mitochondrial translocation contact sites and can hold arrested preproteins in the absence of matrix Hsp70-Tim44". EMBO J. 16 (17): 5408–19. doi:10.1093/emboj/16.17.5408. PMC 1170172. PMID 9312000.
  3. ^ Gabriel K, Egan B, Lithgow T (May 2003). "Tom40, the import channel of the mitochondrial outer membrane, plays an active role in sorting imported proteins". EMBO J. 22 (10): 2380–6. doi:10.1093/emboj/cdg229. PMC 155987. PMID 12743032.
  4. ^ Liu Q, Krzewska J, Liberek K, Craig EA (March 2001). "Mitochondrial Hsp70 Ssc1: role in protein folding". J. Biol. Chem. 276 (9): 6112–8. doi:10.1074/jbc.M009519200. PMID 11096111.
  5. ^ Paschen SA, Rothbauer U, Káldi K, Bauer MF, Neupert W, Brunner M (December 2000). "The role of the TIM8-13 complex in the import of Tim23 into mitochondria". EMBO J. 19 (23): 6392–400. doi:10.1093/emboj/19.23.6392. PMC 305865. PMID 11101512.
  6. ^ Mühlenbein N, Hofmann S, Rothbauer U, Bauer MF (April 2004). "Organization and function of the small Tim complexes acting along the import pathway of metabolite carriers into mammalian mitochondria". J. Biol. Chem. 279 (14): 13540–6. doi:10.1074/jbc.M312485200. PMID 14726512.
  7. ^ a b Gebert N, Chacinska A, Wagner K, Guiard B, Koehler CM, Rehling P, Pfanner N, Wiedemann N (June 2008). "Assembly of the three small Tim proteins precedes docking to the mitochondrial carrier translocase". EMBO Rep. 9 (6): 548–54. doi:10.1038/embor.2008.49. PMC 2427372. PMID 18421298.
  8. ^ a b Wiedemann N, Frazier AE, Pfanner N (April 2004). "The protein import machinery of mitochondria". J. Biol. Chem. 279 (15): 14473–6. doi:10.1074/jbc.R400003200. PMID 14973134.
  9. ^ Bolender N, Sickmann A, Wagner R, Meisinger C, Pfanner N (January 2008). "Multiple pathways for sorting mitochondrial precursor proteins". EMBO Rep. 9 (1): 42–9. doi:10.1038/sj.embor.7401126. PMC 2246611. PMID 18174896.
  10. ^ Endres M, Neupert W, Brunner M (June 1999). "Transport of the ADP/ATP carrier of mitochondria from the TOM complex to the TIM22.54 complex". EMBO J. 18 (12): 3214–21. doi:10.1093/emboj/18.12.3214. PMC 1171402. PMID 10369662.