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35  structures 1598  species 0  interactions 214393  sequences 1423  architectures

Family: Mito_carr (PF00153)

Summary: Mitochondrial carrier protein

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Adenine nucleotide translocator". More...

Adenine nucleotide translocator Edit Wikipedia article

ADP/ATP translocases
ATP-ADP Translocase Top View.png
Cytoplasmic view of the binding pocket of ATP–ADP translocase 1, PDB: 1OKC​.
Identifiers
SymbolAden_trnslctor
PfamPF00153
InterProIPR002113
TCDB2.A.29.1.2
OPM superfamily21
OPM protein2c3e
solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 4
Identifiers
SymbolSLC25A4
Alt. symbolsPEO3, PEO2, ANT1
NCBI gene291
HGNC10990
OMIM103220
RefSeqNM_001151
UniProtP12235
Other data
LocusChr. 4 q35
solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 5
Identifiers
SymbolSLC25A5
Alt. symbolsANT2
NCBI gene292
HGNC10991
OMIM300150
RefSeqNM_001152
UniProtP05141
Other data
LocusChr. X q24-q26
solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 6
Identifiers
SymbolSLC25A6
Alt. symbolsANT3
NCBI gene293
HGNC10992
OMIM403000
RefSeqNM_001636
UniProtP12236
Other data
LocusChr. Y p

Adenine nucleotide translocator (ANT), also known as the ADP/ATP translocase (ANT), ADP/ATP carrier protein (AAC) or mitochondrial ADP/ATP carrier, exchanges free ATP with free ADP across the inner mitochondrial membrane.[1][2] ANT is the most abundant protein in the inner mitochondrial membrane and belongs to mitochondrial carrier family.[3]

Free ADP is transported from the cytoplasm to the mitochondrial matrix, while ATP produced from oxidative phosphorylation is transported from the mitochondrial matrix to the cytoplasm, thus providing the cells with its main energy currency.[4] ADP/ATP translocases are exclusive to eukaryotes and are thought to have evolved during eukaryogenesis.[5] Human cells express four ADP/ATP translocases: SLC25A4, SLC25A5, SLC25A6 and SLC25A31, which constitute more than 10% of the protein in the inner mitochondrial membrane.[6] These proteins are classified under the mitochondrial carrier superfamily.

Types

In humans, there exist three paraologous ANT isoforms:

Structure

A side view of the translocase spanning the inner mitochondrial membrane. The six α-helices are denoted by different colors. The binding pocket is currently open to the cytoplasmic side and will bind to ADP, transporting it into the matrix. (From PDB: 1OKC​)
The translocase (as a molecular surface, green) viewed from both sides of a lipid bilayer representing the inner mitocondrial membrane. Left panel (IM): view from the intermembrane space. The protein is in the open conformation towards this side. Right panel (M): view from the matrix. The protein is closed towards this side.

ANT has long been thought to function as a homodimer, but this concept was challenged by the projection structure of the yeast Aac3p solved by electron crystallography, which showed that the protein was three-fold symmetric and monomeric, with the translocation pathway for the substrate through the centre.[7] The atomic structure of the bovine ANT confirmed this notion, and provided the first structural fold of a mitochondrial carrier.[8] Further work has demonstrated that ANT is a monomer in detergents [9] and functions as a monomer in mitochondrial membranes.[10][11]

ADP/ATP translocase 1 is the major AAC in human cells and the archetypal protein of this family. It has a mass of approximately 30 kDa, consisting of 297 residues.[12] It forms six transmembrane α-helices that form a barrel that results in a deep cone-shaped depression accessible from the outside where the substrate binds. The binding pocket, conserved throughout most isoforms, mostly consists of basic residues that allow for strong binding to ATP or ADP and has a maximal diameter of 20 Å and a depth of 30 Å.[8] Indeed, arginine residues 96, 204, 252, 253, and 294, as well as lysine 38, have been shown to be essential for transporter activity.[13]

Function

ADP/ATP translocase transports ATP synthesized from oxidative phosphorylation into the cytoplasm, where it can be used as the principal energy currency of the cell to power thermodynamically unfavorable reactions. After the consequent hydrolysis of ATP into ADP, ADP is transported back into the mitochondrial matrix, where it can be rephosphorylated to ATP. Because a human typically exchanges the equivalent of his/her own mass of ATP on a daily basis, ADP/ATP translocase is an important transporter protein with major metabolic implications.[4][8]

ANT transports the free, i.e. deprotonated, non-Magnesium, non-Calcium bound forms of ADP and ATP, in a 1:1 ratio.[1] Transport is fully reversible, and its directionality is governed by the concentrations of its substrates (ADP and ATP inside and outside mitochondria), the chelators of the adenine nucleotides, and the mitochondrial membrane potential. The relationship of these parameters can be expressed by an equation solving for the 'reversal potential of the ANT" (Erev_ANT), a value of the mitochondrial membrane potential at which no net transport of adenine nucleotides takes place by the ANT.[14][15][16] The ANT and the F0-F1 ATP synthase are not necessarily in directional synchrony.[14]

Apart from exchange of ADP and ATP across the inner mitochondrial membrane, the ANT also exhibits an intrinsic uncoupling activity[1][17]

ANT is an important modulatory[18] and possible structural component of the Mitochondrial Permeability Transition Pore, a channel involved in various pathologies whose function still remains elusive. Karch et al. propose a "multi-pore model" in which ANT is at least one of the molecular components of the pore.[19]

Translocase mechanism

Under normal conditions, ATP and ADP cannot cross the inner mitochondrial membrane due to their high negative charges, but ADP/ATP translocase, an antiporter, couples the transport of the two molecules. The depression in ADP/ATP translocase alternatively faces the matrix and the cytoplasmic sides of the membrane. ADP in the intermembrane space, coming from the cytoplasm, binds the translocase and induces its eversion, resulting in the release of ADP into the matrix. Binding of ATP from the matrix induces eversion and results in the release of ATP into the intermembrane space, subsequently diffusing to the cytoplasm, and concomitantly brings the translocase back to its original conformation.[4] ATP and ADP are the only natural nucleotides recognized by the translocase.[8]

The net process is denoted by:

ADP3−cytoplasm + ATP4−matrix → ADP3−matrix + ATP4−cytoplasm

ADP/ATP exchange is energetically expensive: about 25% of the energy yielded from electron transfer by aerobic respiration, or one hydrogen ion, is consumed to regenerate the membrane potential that is tapped by ADP/ATP translocase.[4]

The translocator cycles between two states, called the cytoplasmic and matrix state, opening up to these compartments in an alternating way.[1][2] There are structures available that show the translocator locked in a cytoplasmic state by the inhibitor carboxyatractyloside,[8][20] or in the matrix state by the inhibitor bongkrekic acid.[21]

Alterations

Rare but severe diseases such as mitochondrial myopathies are associated with dysfunctional human ADP/ATP translocase. Mitochondrial myopathies (MM) refer to a group of clinically and biochemically heterogeneous disorders that share common features of major mitochondrial structural abnormalities in skeletal muscle. The major morphological hallmark of MM is ragged, red fibers containing peripheral and intermyofibrillar accumulations of abnormal mitochondria.[22][23] In particular, autosomal dominant progressive external ophthalmoplegia (adPEO) is a common disorder associated with dysfunctional ADP/ATP translocase and can induce paralysis of muscles responsible for eye movements. General symptoms are not limited to the eyes and can include exercise intolerance, muscle weakness, hearing deficit, and more. adPEO shows Mendelian inheritance patterns but is characterized by large-scale mitochondrial DNA (mtDNA) deletions. mtDNA contains few introns, or non-coding regions of DNA, which increases the likelihood of deleterious mutations. Thus, any modification of ADP/ATP translocase mtDNA can lead to a dysfunctional transporter,[24] particularly residues involved in the binding pocket which will compromise translocase efficacy.[13] MM is commonly associated with dysfunctional ADP/ATP translocase, but MM can be induced through many different mitochondrial abnormalities.

Inhibition

Bongkrekic acid

ADP/ATP translocase is very specifically inhibited by two families of compounds. The first family, which includes atractyloside (ATR) and carboxyatractyloside (CATR), binds to the ADP/ATP translocase from the cytoplasmic side, locking it in a cytoplasmic side open conformation. In contrast, the second family, which includes bongkrekic acid (BA) and isobongkrekic acid (isoBA), binds the translocase from the matrix, locking it in a matrix side open conformation.[7] The negatively charged groups of the inhibitors bind strongly to the positively charged residues deep within the binding pocket. The high affinity (Kd in the nanomolar range) makes each inhibitor a deadly poison by obstructing cellular respiration/energy transfer to the rest of the cell.[8] There are structures available that show the translocator locked in a cytoplasmic state by the inhibitor carboxyatractyloside,[8][20] or in the matrix state by the inhibitor bongkrekic acid.[21]

History

In 1955, Siekevitz and Potter demonstrated that adenine nucleotides were distributed in cells in two pools located in the mitochondrial and cytosolic compartments.[25] Shortly thereafter, Pressman hypothesized that the two pools could exchange nucleotides.[26] However, the existence of an ADP/ATP transporter was not postulated until 1964 when Bruni et al. uncovered an inhibitory effect of atractyloside on the energy-transfer system (oxidative phosphorylation) and ADP binding sites of rat liver mitochondria.[27] Soon after, an overwhelming amount of research was done in proving the existence and elucidating the link between ADP/ATP translocase and energy transport.[28][29][30] cDNA of ADP/ATP translocase was sequenced for bovine in 1982[31] and a yeast species Saccharomyces cerevisiae in 1986[32] before finally Battini et al. sequenced a cDNA clone of the human transporter in 1989. The homology in the coding sequences between human and yeast ADP/ATP translocase was 47% while bovine and human sequences extended remarkable to 266 out of 297 residues, or 89.6%. In both cases, the most conserved residues lie in the ADP/ATP substrate binding pocket.[12]

See also

References

  1. ^ a b c d Klingenberg M (October 2008). "The ADP and ATP transport in mitochondria and its carrier". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1778 (10): 1978–2021. doi:10.1016/j.bbamem.2008.04.011. PMID 18510943.
  2. ^ a b Kunji ER, Aleksandrova A, King MS, Majd H, Ashton VL, Cerson E, Springett R, Kibalchenko M, Tavoulari S, Crichton PG, Ruprecht JJ (October 2016). "The transport mechanism of the mitochondrial ADP/ATP carrier". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. Channels and transporters in cell metabolism. 1863 (10): 2379–93. doi:10.1016/j.bbamcr.2016.03.015. PMID 27001633.
  3. ^ Palmieri F, Monné M (October 2016). "Discoveries, metabolic roles and diseases of mitochondrial carriers: A review". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. Channels and transporters in cell metabolism. 1863 (10): 2362–78. doi:10.1016/j.bbamcr.2016.03.007. PMID 26968366.
  4. ^ a b c d Stryer L, Berg JM, Tymoczko JL (2007). Biochemistry. San Francisco: W.H. Freeman. p. 553. ISBN 978-0-7167-8724-2.
  5. ^ Radzvilavicius AL, Blackstone NW (October 2015). "Conflict and cooperation in eukaryogenesis: implications for the timing of endosymbiosis and the evolution of sex". Journal of the Royal Society, Interface. 12 (111): 20150584. doi:10.1098/rsif.2015.0584. PMC 4614496. PMID 26468067.
  6. ^ Brandolin G, Dupont Y, Vignais PV (April 1985). "Substrate-induced modifications of the intrinsic fluorescence of the isolated adenine nucleotide carrier protein: demonstration of distinct conformational states". Biochemistry. 24 (8): 1991–7. doi:10.1021/bi00329a029. PMID 2990548.
  7. ^ a b Kunji ER, Harding M (September 2003). "Projection structure of the atractyloside-inhibited mitochondrial ADP/ATP carrier of Saccharomyces cerevisiae". The Journal of Biological Chemistry. 278 (39): 36985–8. doi:10.1074/jbc.C300304200. PMID 12893834.
  8. ^ a b c d e f g Pebay-Peyroula E, Dahout-Gonzalez C, Kahn R, Trézéguet V, Lauquin GJ, Brandolin G (November 2003). "Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside". Nature. 426 (6962): 39–44. Bibcode:2003Natur.426...39P. doi:10.1038/nature02056. PMID 14603310. S2CID 4338748.
  9. ^ Bamber L, Slotboom DJ, Kunji ER (August 2007). "Yeast mitochondrial ADP/ATP carriers are monomeric in detergents as demonstrated by differential affinity purification". Journal of Molecular Biology. 371 (2): 388–95. doi:10.1016/j.jmb.2007.05.072. PMID 17572439.
  10. ^ Bamber L, Harding M, Monné M, Slotboom DJ, Kunji ER (June 2007). "The yeast mitochondrial ADP/ATP carrier functions as a monomer in mitochondrial membranes". Proceedings of the National Academy of Sciences of the United States of America. 104 (26): 10830–4. Bibcode:2007PNAS..10410830B. doi:10.1073/pnas.0703969104. PMC 1891095. PMID 17566106.
  11. ^ Kunji ER, Crichton PG (March 2010). "Mitochondrial carriers function as monomers". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1797 (6–7): 817–31. doi:10.1016/j.bbabio.2010.03.023. PMID 20362544.
  12. ^ a b Battini R, Ferrari S, Kaczmarek L, Calabretta B, Chen ST, Baserga R (March 1987). "Molecular cloning of a cDNA for a human ADP/ATP carrier which is growth-regulated". The Journal of Biological Chemistry. 262 (9): 4355–9. doi:10.1016/S0021-9258(18)61355-9. PMID 3031073.
  13. ^ a b Nelson DR, Lawson JE, Klingenberg M, Douglas MG (April 1993). "Site-directed mutagenesis of the yeast mitochondrial ADP/ATP translocator. Six arginines and one lysine are essential". Journal of Molecular Biology. 230 (4): 1159–70. doi:10.1006/jmbi.1993.1233. PMID 8487299.
  14. ^ a b Chinopoulos C, Gerencser AA, Mandi M, Mathe K, Töröcsik B, Doczi J, Turiak L, Kiss G, Konràd C, Vajda S, Vereczki V, Oh RJ, Adam-Vizi V (July 2010). "Forward operation of adenine nucleotide translocase during F0F1-ATPase reversal: critical role of matrix substrate-level phosphorylation". FASEB Journal. 24 (7): 2405–16. doi:10.1096/fj.09-149898. PMC 2887268. PMID 20207940.
  15. ^ Chinopoulos C (May 2011). "Mitochondrial consumption of cytosolic ATP: not so fast". FEBS Letters. 585 (9): 1255–9. doi:10.1016/j.febslet.2011.04.004. PMID 21486564. S2CID 24773903.
  16. ^ Chinopoulos C (December 2011). "The "B space" of mitochondrial phosphorylation". Journal of Neuroscience Research. 89 (12): 1897–904. doi:10.1002/jnr.22659. PMID 21541983. S2CID 6721812.
  17. ^ Brustovetsky N, Klingenberg M (November 1994). "The reconstituted ADP/ATP carrier can mediate H+ transport by free fatty acids, which is further stimulated by mersalyl". The Journal of Biological Chemistry. 269 (44): 27329–36. doi:10.1016/S0021-9258(18)46989-X. PMID 7961643.
  18. ^ Doczi J, Torocsik B, Echaniz-Laguna A, Mousson de Camaret B, Starkov A, Starkova N, Gál A, Molnár MJ, Kawamata H, Manfredi G, Adam-Vizi V, Chinopoulos C (May 2016). "Alterations in voltage-sensing of the mitochondrial permeability transition pore in ANT1-deficient cells". Scientific Reports. 6: 26700. Bibcode:2016NatSR...626700D. doi:10.1038/srep26700. PMC 4879635. PMID 27221760.
  19. ^ Karch J, Bround MJ, Khalil H, et al. Inhibition of mitochondrial permeability transition by deletion of the ANT family and CypD. Sci Adv. 2019;5(8):eaaw4597. Published 2019 Aug 28. doi:10.1126/sciadv.aaw4597
  20. ^ a b Ruprecht JJ, Hellawell AM, Harding M, Crichton PG, McCoy AJ, Kunji ER (January 2014). "Structures of yeast mitochondrial ADP/ATP carriers support a domain-based alternating-access transport mechanism". Proceedings of the National Academy of Sciences of the United States of America. 111 (4): E426-34. Bibcode:2014PNAS..111E.426R. doi:10.1073/pnas.1320692111. PMC 3910652. PMID 24474793.
  21. ^ a b Ruprecht JJ, King MS, Zögg T, Aleksandrova AA, Pardon E, Crichton PG, Steyaert J, Kunji ER (January 2019). "The Molecular Mechanism of Transport by the Mitochondrial ADP/ATP Carrier". Cell. 176 (3): 435–447.e15. doi:10.1016/j.cell.2018.11.025. PMC 6349463. PMID 30611538.
  22. ^ Harding AE, Petty RK, Morgan-Hughes JA (August 1988). "Mitochondrial myopathy: a genetic study of 71 cases". Journal of Medical Genetics. 25 (8): 528–35. doi:10.1136/jmg.25.8.528. PMC 1080029. PMID 3050098.
  23. ^ Rose MR (January 1998). "Mitochondrial myopathies: genetic mechanisms". Archives of Neurology. 55 (1): 17–24. doi:10.1001/archneur.55.1.17. PMID 9443707.
  24. ^ Kaukonen J, Juselius JK, Tiranti V, Kyttälä A, Zeviani M, Comi GP, Keränen S, Peltonen L, Suomalainen A (August 2000). "Role of adenine nucleotide translocator 1 in mtDNA maintenance". Science. 289 (5480): 782–5. Bibcode:2000Sci...289..782K. doi:10.1126/science.289.5480.782. PMID 10926541.
  25. ^ Siekevitz P, Potter VR (July 1955). "Biochemical structure of mitochondria. II. Radioactive labeling of intra-mitochondrial nucleotides during oxidative phosphorylation". The Journal of Biological Chemistry. 215 (1): 237–55. doi:10.1016/S0021-9258(18)66032-6. PMID 14392158.
  26. ^ Pressman BC (June 1958). "Intramitochondrial nucleotides. I. Some factors affecting net interconversions of adenine nucleotides". The Journal of Biological Chemistry. 232 (2): 967–78. doi:10.1016/S0021-9258(19)77415-8. PMID 13549480.
  27. ^ Bruni A, Luciani S, Contessa AR (March 1964). "Inhibition by atractyloside of the binding of adenine-nucleotides to rat-liver mitochondria". Nature. 201 (1): 1219–20. Bibcode:1964Natur.201.1219B. doi:10.1038/2011219a0. PMID 14151375. S2CID 4170544.
  28. ^ Duee ED, Vignais PV (August 1965). "[Exchange between extra- and intramitochondrial adenine nucleotides]". Biochimica et Biophysica Acta. 107 (1): 184–8. doi:10.1016/0304-4165(65)90419-8. PMID 5857365.
  29. ^ Pfaff E, Klingenberg M, Heldt HW (June 1965). "Unspecific permeation and specific exchange of adenine nucleotides in liver mitochondria". Biochimica et Biophysica Acta (BBA) - General Subjects. 104 (1): 312–5. doi:10.1016/0304-4165(65)90258-8. PMID 5840415.
  30. ^ Saks VA, Lipina NV, Smirnov VN, Chazov EI (March 1976). "Studies of energy transport in heart cells. The functional coupling between mitochondrial creatine phosphokinase and ATP ADP translocase: kinetic evidence". Archives of Biochemistry and Biophysics. 173 (1): 34–41. doi:10.1016/0003-9861(76)90231-9. PMID 1259440.
  31. ^ Aquila H, Misra D, Eulitz M, Klingenberg M (March 1982). "Complete amino acid sequence of the ADP/ATP carrier from beef heart mitochondria". Hoppe-Seyler's Zeitschrift für Physiologische Chemie. 363 (3): 345–9. doi:10.1515/bchm2.1982.363.1.345. PMID 7076130.
  32. ^ Adrian GS, McCammon MT, Montgomery DL, Douglas MG (February 1986). "Sequences required for delivery and localization of the ADP/ATP translocator to the mitochondrial inner membrane". Molecular and Cellular Biology. 6 (2): 626–34. doi:10.1128/mcb.6.2.626. PMC 367554. PMID 3023860.

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This is the Wikipedia entry entitled "Mitochondrial carrier". More...

Mitochondrial carrier Edit Wikipedia article

1okc opm.png
Mitochondrial ADP/ATP carrier
Identifiers
SymbolMito_carr
PfamPF00153
InterProIPR018108
PROSITEPDOC00189
SCOP21okc / SCOPe / SUPFAM
TCDB2.A.29
OPM superfamily21
OPM protein1okc
MC Superfamily
Identifiers
Symbol?
InterProIPR023395

Mitochondrial carriers are proteins from solute carrier family 25 which transfer molecules across the membranes of the mitochondria.[1] Mitochondrial carriers are also classified in the Transporter Classification Database. The Mitochondrial Carrier (MC) Superfamily has been expanded to include both the original Mitochondrial Carrier (MC) family (TC# 2.A.29) and the Mitochondrial Inner/Outer Membrane Fusion (MMF) family (TC# 1.N.6).[2]

Phylogeny

Members of the MC family (SLC25) (TC# 2.A.29) are found exclusively in eukaryotic organelles although they are nuclearly encoded. Most are found in mitochondria, but some are found in peroxisomes of animals, in hydrogenosomes of anaerobic fungi, and in amyloplasts of plants.

SLC25 is the largest solute transporter family in humans. 53 members have been identified in human genome, 58 in A. thaliana and 35 in S. cerevisiae. The functions of approximately 30% of the human SLC25 proteins are unknown, but most of the yeast homologues have been functionally identified.[3][4] See TCDB for functional assignments

Function

Many MC proteins preferentially catalyze the exchange of one solute for another (antiport). A variety of these substrate carrier proteins, which are involved in energy transfer, have been found in the inner membranes of mitochondria and other eukaryotic organelles such as the peroxisome and facilitate the transport of inorganic ions, nucleotides, amino acids, keto acids and cofactors across the membrane.[5][6][7][8] Such proteins include:

Functional aspects of these proteins, including metabolite transport, have been reviewed by Dr. Ferdinando Palmieri and Dr. Ciro Leonardo Pierri (2010).[12][13][14] Diseases caused by defects of mitochondrial carriers are reviewed by Palmieri et al. (2008) and by Gutiérrez-Aguilar and Baines 2013.[15][16] Mutations of mitochondrial carrier genes involved in mitochondrial functions other than oxidative phosphorylation are responsible for carnitine/acylcarnitine carrier deficiency, HHH syndrome, aspartate/glutamate isoform 2 deficiency, Amish microcephaly, and neonatal myoclonic epilepsy. These disorders are characterized by specific metabolic dysfunctions, depending on the physiological role of the affected carrier in intermediary metabolism. Defects of mitochondrial carriers that supply mitochondria with the substrates of oxidative phosphorylation, inorganic phosphate and ADP, are responsible for diseases characterized by defective energy production.[15] Residues involved in substrate binding in the middle of the transporter and gating have been identified and analyzed.[8]

Structure

Permeases of the MC family (the human SLC25 family) possess six transmembrane α-helices. The proteins are of fairly uniform size of about 300 residues. They arose by tandem intragenic triplication in which a genetic element encoding two spanners gave rise to one encoding six spanners.[17] This event may have occurred less than 2 billion years ago when mitochondria first developed their specialized endosymbiotic functions within eukaryotic cells.[18] Members of the MC family are functional and structural monomers although early reports indicated that they are dimers.[3][4]

Most MC proteins contain a primary structure exhibiting three repeats, each of about 100 amino acid residues in length, and both the N and C termini face the intermembrane space. All carriers contain a common sequence, referred to as the MCF motif, in each repeated region, with some variation in one or two signature sequences.[1]

Amongst the members of the mitochondrial carrier family that have been identified, it is the ADP/ATP carrier (AAC; TC# 2.A.29.1.1) that is responsible for importing ADP into the mitochondria and exporting ATP out of the mitochondria and into the cytosol following synthesis.[19] The AAC is an integral membrane protein that is synthesised lacking a cleavable presequence, but instead contains internal targeting information.[20] It consists of a basket shaped structure with six transmembrane helices that are tilted with respect to the membrane, 3 of them "kinked" due to the presence of prolyl residues.[1]

Residues that are important for the transport mechanism are likely to be symmetrical, whereas residues involved in substrate binding will be asymmetrical reflecting the asymmetry of the substrates. By scoring the symmetry of residues in the sequence repeats, Robinson et al. (2008) identified the substrate-binding sites and salt bridge networks that are important for transport. The symmetry analyses provides an assessment of the role of residues and provides clues to the chemical identities of substrates of uncharacterized transporters.[21]

There are structures of the mitochondrial ADP/ATP carrier in two different states. One is the cytoplasmic state, inhibited by carboxyatractyloside, in which the substrate binding site is accessible to the intermembrane space, which is confluent with the cytosol, i.e. the bovine mitochondrial ADP/ATP carrier PDB: 1OKC​/PDB: 2C3E​,[22][23] the yeast ADP/ATP carrier Aac2p PDB: 4C9G​/PDB: 4C9H​,[24] the yeast ADP/ATP carrier Aac3p PDB: 4C9J​/PDB: 4C9Q​,[24] Another is the matrix state, inhibited by bongkrekic acid, in which the substrate binding site is accessible to the mitochondrial matrix, i.e. the fungal mitochondrial ADP/ATP carrier PDB: 6GCI​.[25] In addition, there are structures of the calcium regulatory domains of the mitochondrial ATP-Mg/Pi carrier in the calcium-bound state PDB: 4ZCU​/PDB: 4N5X​ [26][27] and mitochondrial aspartate/glutamate carriers in different regulatory states PDB: 4P5X​/PDB: 4P60​/PDB: 4P5W​.[28]

Substrates

Mitochondrial carriers transport amino acids, keto acids, nucleotides, inorganic ions and co-factors through the mitochondrial inner membrane. The transporters consist of six transmembrane alpha-helices with threefold pseudo-symmetry.[29]

The transported substrates of MC family members may bind to the bottom of the cavity, and translocation results in a transient transition from a 'pit' to a 'channel' conformation.[30] An inhibitor of AAC, carboxyatractyloside, probably binds where ADP binds, in the pit on the outer surface, thus blocking the transport cycle. Another inhibitor, bongkrekic acid, is believed to stabilize a second conformation, with the pit facing the matrix. In this conformation, the inhibitor may bind to the ATP-binding site. Functional and structural roles for residues in the TMSs have been proposed.[31][32] The mitochondrial carrier signature, Px[D/E]xx[K/R], of carriers is probably involved both in the biogenesis and in the transport activity of these proteins.[33] A homologue has been identified in the mimivirus genome and shown to be a transporter for dATP and dTTP.[34]

Examples of transported compounds include:

Examples

Human proteins containing this domain include:

Yeast Ugo1 is an example of the MMF family, but this protein has no human ortholog.

References

  1. ^ a b c Nury, H.; Dahout-Gonzalez, C.; Trézéguet, V.; Lauquin, G.J.M.; Brandolin, G.; Pebay-Peyroula, E. (2006). "Relations between structure and function of the mitochondrial ADP/ATP carrier". Annu. Rev. Biochem. 75: 713–41. doi:10.1146/annurev.biochem.75.103004.142747. PMID 16756509.
  2. ^ Kuan J, Saier MH (October 1993). "Expansion of the mitochondrial carrier family". Research in Microbiology. 144 (8): 671–2. doi:10.1016/0923-2508(93)90073-B. PMID 8140286.
  3. ^ a b Bamber L, Harding M, Monné M, Slotboom DJ, Kunji ER (June 2007). "The yeast mitochondrial ADP/ATP carrier functions as a monomer in mitochondrial membranes". Proceedings of the National Academy of Sciences of the United States of America. 104 (26): 10830–4. Bibcode:2007PNAS..10410830B. doi:10.1073/pnas.0703969104. PMC 1891095. PMID 17566106.
  4. ^ a b Bamber L, Harding M, Butler PJ, Kunji ER (October 2006). "Yeast mitochondrial ADP/ATP carriers are monomeric in detergents". Proceedings of the National Academy of Sciences of the United States of America. 103 (44): 16224–9. Bibcode:2006PNAS..10316224B. doi:10.1073/pnas.0607640103. PMC 1618811. PMID 17056710.
  5. ^ Klingenberg M (March 1990). "Mechanism and evolution of the uncoupling protein of brown adipose tissue". Trends in Biochemical Sciences. 15 (3): 108–12. doi:10.1016/0968-0004(90)90194-G. PMID 2158156.
  6. ^ Nelson DR, Lawson JE, Klingenberg M, Douglas MG (April 1993). "Site-directed mutagenesis of the yeast mitochondrial ADP/ATP translocator. Six arginines and one lysine are essential". Journal of Molecular Biology. 230 (4): 1159–70. doi:10.1006/jmbi.1993.1233. PMID 8487299.
  7. ^ Jank B, Habermann B, Schweyen RJ, Link TA (November 1993). "PMP47, a peroxisomal homologue of mitochondrial solute carrier proteins". Trends in Biochemical Sciences. 18 (11): 427–8. doi:10.1016/0968-0004(93)90141-9. PMID 8291088.
  8. ^ a b Monné M, Palmieri F, Kunji ER (March 2013). "The substrate specificity of mitochondrial carriers: mutagenesis revisited". Molecular Membrane Biology. 30 (2): 149–59. doi:10.3109/09687688.2012.737936. PMID 23121155. S2CID 1837739.
  9. ^ a b Dolce V, Cappello AR, Capobianco L (July 2014). "Mitochondrial tricarboxylate and dicarboxylate-tricarboxylate carriers: from animals to plants". IUBMB Life. 66 (7): 462–71. doi:10.1002/iub.1290. PMID 25045044. S2CID 21307218.
  10. ^ Palmieri F (June 1994). "Mitochondrial carrier proteins". FEBS Letters. 346 (1): 48–54. doi:10.1016/0014-5793(94)00329-7. PMID 8206158. S2CID 35726914.
  11. ^ Walker JE (1992). "The mitochondrial transporter family". Curr. Opin. Struct. Biol. 2 (4): 519–526. doi:10.1016/0959-440X(92)90081-H.
  12. ^ Palmieri F (February 2004). "The mitochondrial transporter family (SLC25): physiological and pathological implications". Pflügers Archiv. 447 (5): 689–709. doi:10.1007/s00424-003-1099-7. PMID 14598172. S2CID 25304722.
  13. ^ Palmieri F, Rieder B, Ventrella A, Blanco E, Do PT, Nunes-Nesi A, Trauth AU, Fiermonte G, Tjaden J, Agrimi G, Kirchberger S, Paradies E, Fernie AR, Neuhaus HE (November 2009). "Molecular identification and functional characterization of Arabidopsis thaliana mitochondrial and chloroplastic NAD+ carrier proteins". The Journal of Biological Chemistry. 284 (45): 31249–59. doi:10.1074/jbc.M109.041830. PMC 2781523. PMID 19745225.
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  15. ^ a b Palmieri F (2008-08-01). "Diseases caused by defects of mitochondrial carriers: a review". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1777 (7–8): 564–78. doi:10.1016/j.bbabio.2008.03.008. PMID 18406340.
  16. ^ Gutiérrez-Aguilar M, Baines CP (September 2013). "Physiological and pathological roles of mitochondrial SLC25 carriers". The Biochemical Journal. 454 (3): 371–86. doi:10.1042/BJ20121753. PMC 3806213. PMID 23988125.
  17. ^ Palmieri F (2013-06-01). "The mitochondrial transporter family SLC25: identification, properties and physiopathology". Molecular Aspects of Medicine. 34 (2–3): 465–84. doi:10.1016/j.mam.2012.05.005. PMID 23266187.
  18. ^ Kuan J, Saier MH (1993-01-01). "The mitochondrial carrier family of transport proteins: structural, functional, and evolutionary relationships". Critical Reviews in Biochemistry and Molecular Biology. 28 (3): 209–33. doi:10.3109/10409239309086795. PMID 8325039.
  19. ^ Kunji, Edmund R. S.; Aleksandrova, Antoniya; King, Martin S.; Majd, Homa; Ashton, Valerie L.; Cerson, Elizabeth; Springett, Roger; Kibalchenko, Mikhail; Tavoulari, Sotiria (2016). "The transport mechanism of the mitochondrial ADP/ATP carrier" (PDF). Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1863 (10): 2379–2393. doi:10.1016/j.bbamcr.2016.03.015. ISSN 0006-3002. PMID 27001633.
  20. ^ Ryan MT, Müller H, Pfanner N (July 1999). "Functional staging of ADP/ATP carrier translocation across the outer mitochondrial membrane". The Journal of Biological Chemistry. 274 (29): 20619–27. doi:10.1074/jbc.274.29.20619. PMID 10400693.
  21. ^ Robinson AJ, Overy C, Kunji ER (November 2008). "The mechanism of transport by mitochondrial carriers based on analysis of symmetry". Proceedings of the National Academy of Sciences of the United States of America. 105 (46): 17766–71. Bibcode:2008PNAS..10517766R. doi:10.1073/pnas.0809580105. PMC 2582046. PMID 19001266.
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  23. ^ Nury, H.; Dahout-Gonzalez, C.; Trézéguet, V.; Lauquin, G.; Brandolin, G.; Pebay-Peyroula, E. (2005). "Structural basis for lipid-mediated interactions between mitochondrial ADP/ATP carrier monomers". FEBS Letters. 579 (27): 6031–6036. doi:10.1016/j.febslet.2005.09.061. ISSN 0014-5793. PMID 16226253. S2CID 30874107.
  24. ^ a b Ruprecht, Jonathan J.; Hellawell, Alex M.; Harding, Marilyn; Crichton, Paul G.; McCoy, Airlie J.; Kunji, Edmund R. S. (2014). "Structures of yeast mitochondrial ADP/ATP carriers support a domain-based alternating-access transport mechanism". Proceedings of the National Academy of Sciences of the United States of America. 111 (4): E426–434. Bibcode:2014PNAS..111E.426R. doi:10.1073/pnas.1320692111. ISSN 1091-6490. PMC 3910652. PMID 24474793.
  25. ^ Ruprecht, Jonathan J.; King, Martin S.; Zögg, Thomas; Aleksandrova, Antoniya A.; Pardon, Els; Crichton, Paul G.; Steyaert, Jan; Kunji, Edmund R. S. (2019). "The Molecular Mechanism of Transport by the Mitochondrial ADP/ATP Carrier". Cell. 176 (3): 435–447.e15. doi:10.1016/j.cell.2018.11.025. ISSN 1097-4172. PMC 6349463. PMID 30611538.
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External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Mitochondrial carrier protein Provide feedback

No Pfam abstract.

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR018108

A variety of substrate carrier proteins that are involved in energy transfer are found in the inner mitochondrial membrane or integral to the membrane of other eukaryotic organelles such as the peroxisome [ PUBMED:2158156 , PUBMED:8140286 , PUBMED:8487299 , PUBMED:8206158 , PUBMED:8291088 ]. Such proteins include: ADP, ATP carrier protein (ADP/ATP translocase); 2-oxoglutarate/malate carrier protein; phosphate carrier protein; tricarboxylate transport protein (or citrate transport protein); Graves disease carrier protein; yeast mitochondrial proteins MRS3 and MRS4; yeast mitochondrial FAD carrier protein; and many others. Structurally, these proteins can consist of up to three tandem repeats of a domain of approximately 100 residues, each domain containing two transmembrane regions.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(160)
Full
(214393)
Representative proteomes UniProt
(348951)
RP15
(39690)
RP35
(94737)
RP55
(163718)
RP75
(221328)
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PP/heatmap 1            

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(160)
Full
(214393)
Representative proteomes UniProt
(348951)
RP15
(39690)
RP35
(94737)
RP55
(163718)
RP75
(221328)
Alignment:
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Sequence:
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(160)
Full
(214393)
Representative proteomes UniProt
(348951)
RP15
(39690)
RP35
(94737)
RP55
(163718)
RP75
(221328)
Raw Stockholm Download   Download   Download   Download   Download   Download    
Gzipped Download   Download   Download   Download   Download   Download    

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: mito_carr;
Type: Repeat
Sequence Ontology: SO:0001068
Author: Sonnhammer ELL
Number in seed: 160
Number in full: 214393
Average length of the domain: 94.20 aa
Average identity of full alignment: 21 %
Average coverage of the sequence by the domain: 71.69 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 22.3 22.3
Trusted cut-off 22.3 22.3
Noise cut-off 22.2 22.2
Model length: 97
Family (HMM) version: 30
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence

Selections

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Mito_carr domain has been found. There are 35 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A0G2JV03 View 3D Structure Click here
A0A0G2K309 View 3D Structure Click here
A0A0G2K459 View 3D Structure Click here
A0A0G2K5L2 View 3D Structure Click here
A0A0G2KLU8 View 3D Structure Click here
A0A0G2L4H5 View 3D Structure Click here
A0A0P0UZT6 View 3D Structure Click here
A0A0P0V3K9 View 3D Structure Click here
A0A0P0VG45 View 3D Structure Click here
A0A0P0VGN9 View 3D Structure Click here
A0A0P0VTR5 View 3D Structure Click here
A0A0P0WYD6 View 3D Structure Click here
A0A0P0X501 View 3D Structure Click here
A0A0P0XP23 View 3D Structure Click here
A0A0P0Y1K6 View 3D Structure Click here
A0A0P0YBJ7 View 3D Structure Click here
A0A0R0EB47 View 3D Structure Click here
A0A0R0F1Z4 View 3D Structure Click here
A0A0R0FLJ8 View 3D Structure Click here
A0A0R0FUL1 View 3D Structure Click here
A0A0R0GC05 View 3D Structure Click here
A0A0R0GET2 View 3D Structure Click here
A0A0R0GIS2 View 3D Structure Click here
A0A0R0GPW5 View 3D Structure Click here
A0A0R0GXN6 View 3D Structure Click here
A0A0R0H3N5 View 3D Structure Click here
A0A0R0HAS1 View 3D Structure Click here
A0A0R0IWF6 View 3D Structure Click here
A0A0R0IXS8 View 3D Structure Click here
A0A0R0J393 View 3D Structure Click here
A0A0R0KCZ9 View 3D Structure Click here
A0A0R0KF80 View 3D Structure Click here
A0A0R0KTL1 View 3D Structure Click here
A0A0R0KZR8 View 3D Structure Click here
A0A0R0L428 View 3D Structure Click here
A0A0R0L6R1 View 3D Structure Click here
A0A0R0LFF0 View 3D Structure Click here
A0A0R4IA42 View 3D Structure Click here
A0A0R4IB76 View 3D Structure Click here
A0A0R4IHT0 View 3D Structure Click here