Translocase of the inner membrane#The TIM23 complex
{{Pfam_box
| Symbol = Tim17
| Name = Tim17/Tim22/Tim23 family
| image =
| width =
| caption =
| Pfam= PF02466
| InterPro= IPR003397
| SMART=
| Prosite =
| SCOP =
| TCDB = 3.A.8
| OPM family= 266
| OPM protein= 3awr
| PDB=
| Membranome superfamily = 169
}}
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
{{missing information|section|TIM23(SORT), TIM23(MOTOR); Oxa1 targeting|date=December 2020}}
The TIM23 complex facilitates translocation of matrix-targeted proteins into the mitochondrial matrix.{{cite journal |vauthors=Sirrenberg C, Bauer MF, Guiard B, Neupert W, Brunner M | title = Import of carrier proteins into the mitochondrial inner membrane mediated by Tim22 | journal = Nature | volume = 384 | issue = 6609 | pages = 582–5 |date=December 1996 | pmid = 8955274 | doi = 10.1038/384582a0 | bibcode = 1996Natur.384..582S }} 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.{{cite journal |vauthors=Dekker PJ, Martin F, Maarse AC, Bömer U, Müller H, Guiard B, Meijer M, Rassow J, Pfanner N | title = The Tim core complex defines the number of mitochondrial translocation contact sites and can hold arrested preproteins in the absence of matrix Hsp70-Tim44 | journal = EMBO J. | volume = 16 | issue = 17 | pages = 5408–19 |date=September 1997 | pmid = 9312000 | pmc = 1170172 | doi = 10.1093/emboj/16.17.5408 }} 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.{{cite journal |vauthors=Gabriel K, Egan B, Lithgow T | title = Tom40, the import channel of the mitochondrial outer membrane, plays an active role in sorting imported proteins | journal = EMBO J. | volume = 22 | issue = 10 | pages = 2380–6 |date=May 2003 | pmid = 12743032 | pmc = 155987 | doi = 10.1093/emboj/cdg229 }} 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,{{cite journal |vauthors=Liu Q, Krzewska J, Liberek K, Craig EA | title = Mitochondrial Hsp70 Ssc1: role in protein folding | journal = J. Biol. Chem. | volume = 276 | issue = 9 | pages = 6112–8 |date=March 2001 | pmid = 11096111 | doi = 10.1074/jbc.M009519200 | doi-access = free }} facilitated by HSP60.
The TIM22 complex
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{{cite journal |vauthors=Paschen SA, Rothbauer U, Káldi K, Bauer MF, Neupert W, Brunner M | title = The role of the TIM8-13 complex in the import of Tim23 into mitochondria | journal = EMBO J. | volume = 19 | issue = 23 | pages = 6392–400 |date=December 2000 | pmid = 11101512 | pmc = 305865 | doi = 10.1093/emboj/19.23.6392 }} 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.{{cite journal |vauthors=Mühlenbein N, Hofmann S, Rothbauer U, Bauer MF | title = Organization and function of the small Tim complexes acting along the import pathway of metabolite carriers into mammalian mitochondria | journal = J. Biol. Chem. | volume = 279 | issue = 14 | pages = 13540–6 |date=April 2004 | pmid = 14726512 | doi = 10.1074/jbc.M312485200 | doi-access = free }} 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.{{cite journal |vauthors=Gebert N, Chacinska A, Wagner K, Guiard B, Koehler CM, Rehling P, Pfanner N, Wiedemann N | title = Assembly of the three small Tim proteins precedes docking to the mitochondrial carrier translocase | journal = EMBO Rep. | volume = 9 | issue = 6 | pages = 548–54 |date=June 2008 | pmid = 18421298 | pmc = 2427372 | doi = 10.1038/embor.2008.49 }} 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.{{cite journal |vauthors=Wiedemann N, Frazier AE, Pfanner N | title = The protein import machinery of mitochondria | journal = J. Biol. Chem. | volume = 279 | issue = 15 | pages = 14473–6 |date=April 2004 | pmid = 14973134 | doi = 10.1074/jbc.R400003200 | doi-access = free }} A small portion of Tim9 and Tim10 (~5%) assembles into a modified complex containing Tim12, on the outer surface of the TIM22 complex.{{cite journal |vauthors=Bolender N, Sickmann A, Wagner R, Meisinger C, Pfanner N | title = Multiple pathways for sorting mitochondrial precursor proteins | journal = EMBO Rep. | volume = 9 | issue = 1 | pages = 42–9 |date=January 2008 | pmid = 18174896 | pmc = 2246611 | doi = 10.1038/sj.embor.7401126 }} Tim12 is membrane bound and thus may act as a linker molecule docking Tim9 and Tim10 to the face of the TIM22 complex. The carrier preprotein is then inserted into the inner mitochondrial membrane in a potential-dependent fashion.{{cite journal |vauthors=Endres M, Neupert W, Brunner M | title = Transport of the ADP/ATP carrier of mitochondria from the TOM complex to the TIM22.54 complex | journal = EMBO J. | volume = 18 | issue = 12 | pages = 3214–21 |date=June 1999 | pmid = 10369662 | pmc = 1171402 | doi = 10.1093/emboj/18.12.3214 }} 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.