Biology:Mitochondrial carrier

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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. ↑ 1.0 1.1 1.2 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. ↑ "Expansion of the mitochondrial carrier family". Research in Microbiology 144 (8): 671–2. October 1993. doi:10.1016/0923-2508(93)90073-B. PMID 8140286. 
  3. ↑ 3.0 3.1 "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. June 2007. doi:10.1073/pnas.0703969104. PMID 17566106. Bibcode: 2007PNAS..10410830B. 
  4. ↑ 4.0 4.1 "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. October 2006. doi:10.1073/pnas.0607640103. PMID 17056710. Bibcode: 2006PNAS..10316224B. 
  5. ↑ "Mechanism and evolution of the uncoupling protein of brown adipose tissue". Trends in Biochemical Sciences 15 (3): 108–12. March 1990. doi:10.1016/0968-0004(90)90194-G. PMID 2158156. 
  6. ↑ "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. April 1993. doi:10.1006/jmbi.1993.1233. PMID 8487299. 
  7. ↑ "PMP47, a peroxisomal homologue of mitochondrial solute carrier proteins". Trends in Biochemical Sciences 18 (11): 427–8. November 1993. doi:10.1016/0968-0004(93)90141-9. PMID 8291088. 
  8. ↑ 8.0 8.1 "The substrate specificity of mitochondrial carriers: mutagenesis revisited". Molecular Membrane Biology 30 (2): 149–59. March 2013. doi:10.3109/09687688.2012.737936. PMID 23121155. 
  9. ↑ 9.0 9.1 "Mitochondrial tricarboxylate and dicarboxylate-tricarboxylate carriers: from animals to plants". IUBMB Life 66 (7): 462–71. July 2014. doi:10.1002/iub.1290. PMID 25045044. 
  10. ↑ "Mitochondrial carrier proteins". FEBS Letters 346 (1): 48–54. June 1994. doi:10.1016/0014-5793(94)00329-7. PMID 8206158. 
  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. ↑ "The mitochondrial transporter family (SLC25): physiological and pathological implications". Pflügers Archiv 447 (5): 689–709. February 2004. doi:10.1007/s00424-003-1099-7. PMID 14598172. 
  13. ↑ "Molecular identification and functional characterization of Arabidopsis thaliana mitochondrial and chloroplastic NAD+ carrier proteins". The Journal of Biological Chemistry 284 (45): 31249–59. November 2009. doi:10.1074/jbc.M109.041830. PMID 19745225. 
  14. ↑ "Mitochondrial metabolite transport". Essays in Biochemistry 47: 37–52. 2010-01-01. doi:10.1042/bse0470037. PMID 20533899. 
  15. ↑ 15.0 15.1 "Diseases caused by defects of mitochondrial carriers: a review". Biochimica et Biophysica Acta (BBA) - Bioenergetics 1777 (7–8): 564–78. 2008-08-01. doi:10.1016/j.bbabio.2008.03.008. PMID 18406340. 
  16. ↑ "Physiological and pathological roles of mitochondrial SLC25 carriers". The Biochemical Journal 454 (3): 371–86. September 2013. doi:10.1042/BJ20121753. PMID 23988125. 
  17. ↑ "The mitochondrial transporter family SLC25: identification, properties and physiopathology". Molecular Aspects of Medicine 34 (2–3): 465–84. 2013-06-01. doi:10.1016/j.mam.2012.05.005. PMID 23266187. 
  18. ↑ "The mitochondrial carrier family of transport proteins: structural, functional, and evolutionary relationships". Critical Reviews in Biochemistry and Molecular Biology 28 (3): 209–33. 1993-01-01. 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 et al. (2016). "The transport mechanism of the mitochondrial ADP/ATP carrier". 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. https://ueaeprints.uea.ac.uk/61248/1/Review_for_BBA_final_reduced.pdf. 
  20. ↑ "Functional staging of ADP/ATP carrier translocation across the outer mitochondrial membrane". The Journal of Biological Chemistry 274 (29): 20619–27. July 1999. doi:10.1074/jbc.274.29.20619. PMID 10400693. 
  21. ↑ "The mechanism of transport by mitochondrial carriers based on analysis of symmetry" (in en). Proceedings of the National Academy of Sciences of the United States of America 105 (46): 17766–71. November 2008. doi:10.1073/pnas.0809580105. PMID 19001266. Bibcode: 2008PNAS..10517766R. 
  22. ↑ Pebay-Peyroula, Eva; Dahout-Gonzalez, Cécile; Kahn, Richard; Trézéguet, Véronique; Lauquin, Guy J.-M.; Brandolin, Gérard (2003). "Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside". Nature 426 (6962): 39–44. doi:10.1038/nature02056. ISSN 1476-4687. PMID 14603310. Bibcode: 2003Natur.426...39P. 
  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. 
  24. ↑ 24.0 24.1 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. doi:10.1073/pnas.1320692111. ISSN 1091-6490. PMID 24474793. Bibcode: 2014PNAS..111E.426R. 
  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. PMID 30611538. 
  26. ↑ Harborne, Steven P. D.; Ruprecht, Jonathan J.; Kunji, Edmund R. S. (2015). "Calcium-induced conformational changes in the regulatory domain of the human mitochondrial ATP-Mg/Pi carrier". Biochimica et Biophysica Acta (BBA) - Bioenergetics 1847 (10): 1245–1253. doi:10.1016/j.bbabio.2015.07.002. ISSN 0006-3002. PMID 26164100. 
  27. ↑ Yang, Qin; Brüschweiler, Sven; Chou, James J. (2014). "A self-sequestered calmodulin-like Ca²⁺ sensor of mitochondrial SCaMC carrier and its implication to Ca²⁺-dependent ATP-Mg/P(i) transport". Structure 22 (2): 209–217. doi:10.1016/j.str.2013.10.018. ISSN 1878-4186. PMID 24332718. 
  28. ↑ Thangaratnarajah, Chancievan; Ruprecht, Jonathan J.; Kunji, Edmund R. S. (2014). "Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers". Nature Communications 5: 5491. doi:10.1038/ncomms6491. ISSN 2041-1723. PMID 25410934. Bibcode: 2014NatCo...5.5491T. 
  29. ↑ "Coupling of proton and substrate translocation in the transport cycle of mitochondrial carriers". Current Opinion in Structural Biology 20 (4): 440–7. August 2010. doi:10.1016/j.sbi.2010.06.004. PMID 20598524. 
  30. ↑ "The conserved substrate binding site of mitochondrial carriers". Biochimica et Biophysica Acta (BBA) - Bioenergetics 1757 (9–10): 1237–48. 2006-10-01. doi:10.1016/j.bbabio.2006.03.021. PMID 16759636. 
  31. ↑ "Functional and structural role of amino acid residues in the even-numbered transmembrane alpha-helices of the bovine mitochondrial oxoglutarate carrier". Journal of Molecular Biology 363 (1): 51–62. October 2006. doi:10.1016/j.jmb.2006.08.041. PMID 16962611. 
  32. ↑ "Functional and structural role of amino acid residues in the odd-numbered transmembrane alpha-helices of the bovine mitochondrial oxoglutarate carrier". Journal of Molecular Biology 369 (2): 400–12. June 2007. doi:10.1016/j.jmb.2007.03.048. PMID 17442340. 
  33. ↑ "Biogenesis of yeast dicarboxylate carrier: the carrier signature facilitates translocation across the mitochondrial outer membrane". Journal of Cell Science 120 (Pt 23): 4099–106. December 2007. doi:10.1242/jcs.018929. PMID 18032784. 
  34. ↑ "The mimivirus genome encodes a mitochondrial carrier that transports dATP and dTTP". Journal of Virology 81 (7): 3181–6. April 2007. doi:10.1128/JVI.02386-06. PMID 17229695. 

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