Translocase of the inner membrane

Last updated
Tim17/Tim22/Tim23 family
Identifiers
SymbolTim17
Pfam PF02466
InterPro IPR003397
TCDB 3.A.8
OPM superfamily 266
OPM protein 3awr
Membranome 169
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure 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.

Contents

The TIM23 complex

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

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

Human proteins containing this domain

TIM17A; TIMM17A; TIMM17B; TIMM22; TIMM23;

See also

Related Research Articles

Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell. Proteins can be targeted to the inner space of an organelle, different intracellular membranes, the plasma membrane, or to the exterior of the cell via secretion. Information contained in the protein itself directs this delivery process. Correct sorting is crucial for the cell; errors or dysfunction in sorting have been linked to multiple diseases.

<span class="mw-page-title-main">Intermembrane space</span>

The intermembrane space (IMS) is the space occurring between or involving two or more membranes. In cell biology, it is most commonly described as the region between the inner membrane and the outer membrane of a mitochondrion or a chloroplast. It also refers to the space between the inner and outer nuclear membranes of the nuclear envelope, but is often called the perinuclear space. The IMS of mitochondria plays a crucial role in coordinating a variety of cellular activities, such as regulation of respiration and metabolic functions. Unlike the IMS of the mitochondria, the IMS of the chloroplast does not seem to have any obvious function.

<span class="mw-page-title-main">TIM/TOM complex</span>

The TIM/TOM complex is a protein complex in cellular biochemistry which translocates proteins produced from nuclear DNA through the mitochondrial membrane for use in oxidative phosphorylation. In enzymology, the complex is described as an mitochondrial protein-transporting ATPase, or more systematically ATP phosphohydrolase , as the TIM part requires ATP hydrolysis to work.

<span class="mw-page-title-main">Mitochondrial membrane transport protein</span>

Mitochondrial membrane transport proteins, also known as mitochondrial carrier proteins, are proteins which exist in the membranes of mitochondria. They serve to transport molecules and other factors, such as ions, into or out of the organelles. Mitochondria contain both an inner and outer membrane, separated by the inter-membrane space, or inner boundary membrane. The outer membrane is porous, whereas the inner membrane restricts the movement of all molecules. The two membranes also vary in membrane potential and pH. These factors play a role in the function of mitochondrial membrane transport proteins. There are 53 discovered human mitochondrial membrane transporters, with many others that are known to still need discovered.

<span class="mw-page-title-main">TIMM8A</span> Protein-coding gene in humans

Mitochondrial import inner membrane translocase subunit Tim8 A, also known as deafness-dystonia peptide or protein is an enzyme that in humans is encoded by the TIMM8A gene. This translocase has similarity to yeast mitochondrial proteins that are involved in the import of metabolite transporters from the cytoplasm into the mitochondrial inner membrane. The gene is mutated in deafness-dystonia syndrome and it is postulated that MTS/DFN-1 is a mitochondrial disease caused by a defective mitochondrial protein import system.

<span class="mw-page-title-main">TOMM22</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import receptor subunit TOM22 homolog(hTom22) is a protein that in humans is encoded by the TOMM22 gene.

<span class="mw-page-title-main">TIMM13</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit Tim13 is an enzyme that in humans is encoded by the TIMM13 gene.

<span class="mw-page-title-main">Translocase of the outer membrane</span>

The translocase of the outer membrane (TOM) is a complex of proteins found in the outer mitochondrial membrane of the mitochondria. It allows movement of proteins through this barrier and into the intermembrane space of the mitochondrion. Most of the proteins needed for mitochondrial function are encoded by the nucleus of the cell. The outer membrane of the mitochondrion is impermeable to large molecules greater than 5000 daltons. The TOM works in conjunction with the translocase of the inner membrane (TIM) to translocate proteins into the mitochondrion. Many of the proteins in the TOM complex, such as TOMM22, were first identified in Neurospora crassa and Saccharomyces cerevisiae. Many of the genes encoding these proteins are designated as TOMM (translocase of the outer mitochondrial membrane) complex genes.

<span class="mw-page-title-main">TIMM10</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit Tim10 is an enzyme that in humans is encoded by the TIMM10 gene.

<span class="mw-page-title-main">TIMM44</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit TIM44 is an enzyme that in humans is encoded by the TIMM44 gene.

<span class="mw-page-title-main">TIMM10B</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit Tim9 B is an enzyme that in humans is encoded by the FXC1 gene.

<span class="mw-page-title-main">TIMM23</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit Tim23 is an enzyme that in humans is encoded by the TIMM23 gene.

<span class="mw-page-title-main">TIMM17A</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit Tim17-A is an enzyme that in humans is encoded by the TIMM17A gene.

<span class="mw-page-title-main">DNAJC19</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit TIM14 is an enzyme that in humans is encoded by the DNAJC19 gene on chromosome 3. TIM14 belongs to the DnaJ family, which has been involved in Hsp40/Hsp70 chaperone systems. As a mitochondrial chaperone, TIM14 functions as part of the TIM23 complex import motor to facilitate the import of nuclear-encoded proteins into the mitochondria. TIM14 also complexes with prohibitin complexes to regulate mitochondrial morphogenesis, and has been implicated in dilated cardiomyopathy with ataxia.

<span class="mw-page-title-main">TIMM9</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit Tim9 is an enzyme that in humans is encoded by the TIMM9 gene.

<span class="mw-page-title-main">TIMM22</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit Tim22 is an enzyme that in humans is encoded by the TIMM22 gene.

<span class="mw-page-title-main">TIMM50</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit TIM50 is a protein that in humans is encoded by the TIMM50 gene. Tim50 is a subunit of the Tim23 translocase complex in the inner mitochondrial membrane. Mutations in TIMM50 can lead to epilepsy, severe intellectual disability, and 3-methylglutaconic aciduria. TIMM50 expression is increased in breast cancer cells and decreased in hypertrophic hearts.

Tim9 and Tim10 make up the group of essential small Tim proteins that assist in transport of hydrophobic precursors across the intermembrane space in mammalian cells. Both Tim9 and Tim10 form a hexamer, the Tim9-Tim10 complex, that when associated, functions as a chaperone to assist translocation of preproteins from the outer mitochondrial membrane to the translocase of the inner membrane. The functional Tim9-Tim10 complex not only directs preproteins to the inner mitochondrial membrane in order to interact with the TIM22 complex, but also guides β-barrel precursor proteins to the sorting and assembly machinery (SAM) of the outer membrane.

The outer mitochondrial membrane is made up of two essential proteins, Tom40 and Sam50.

Mitochondrial processing peptidase is an enzyme complex found in mitochondria which cleaves signal sequences from mitochondrial proteins. In humans this complex is composed of two subunits encoded by the genes PMPCA, and PMPCB. The enzyme is also known as. This enzyme catalyses the following chemical reaction

References

  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. 1 2 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. 1 2 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.
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