Summary: Mitochondrial carrier protein
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Mitochondrial carrier Edit Wikipedia article
Mitochondrial ADP/ATP carrier
Mitochondrial carriers are proteins from a solute carrier family which transfer molecules across the membranes of the mitochondria. 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# 9.B.25).
Members of the MC family (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.
15 paralogues of the MC family are encoded within the genome of Saccharomyces cerevisiae. 50 have been identified in humans, 58 in A. thaliana and 35 in S. cerevisiae. The functions of many of the human homologues are unknown, but most of the yeast homologues have been functionally identified. See TCDB for functional assignments
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. Such proteins include:
- ADP/ATP carrier protein (ADP-ATP translocase; i.e., TC# 2.A.29.1.2)
- 2-oxoglutarate/malate carrier protein (SLC25A11; TC# 2.A.29.2.11) 
- phosphate carrier protein (SLC25A3; TC# 2.A.29.4.2)
- Tricarboxylate transport protein (SLC25A1, or citrate transport protein; TC# 2.A.29.7.2)
- Graves disease carrier protein (SLC25A16; TC# 2.A.29.12.1)
- Yeast mitochondrial proteins MRS3 (TC# 2.A.29.5.1) and MRS4 (TC# 2.A.29.5.2)
- Yeast mitochondrial FAD carrier protein (TC# 2.A.29.10.1)
- As well as many others.
Functional aspects of these proteins, including metabolite transport, have been reviewed by Dr. Ferdinando Palmieri and Dr. Ciro Leonardo Pierri (2010). Diseases caused by defects of mitochondrial carriers are reviewed by Palmieri et al. (2008) and by Gutiérrez-Aguilar and Baines 2013. 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. Residues involved in substrate binding in the middle of the transporter and gating have been identified and analyzed.
Permeases of the MC family (the human SLC25 family) possess six transmembrane β-helical spanners. 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. This event may have occurred less than 2 billion years ago when mitochondria first developed their specialized endosymbiotic functions within eukaryotic cells. Members of the MC family are functional and structural monomers although early reports indicated that they are dimers.
Most MC proteins contain a primary structure exhibiting three repeats, each of about 100 amino acyl 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.
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. The AAC is an integral membrane protein that is synthesised lacking a cleavable presequence, but instead contains internal targeting information. It forms a dimer of two identical subunits and 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.
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.
A few MC protein crystal structures are available in RCSB, including:, , , , ,
Members of the mitochondrial carrier family are involved in transporting keto acids, amino acids, nucleotides, inorganic ions and co-factors across the mitochondrial inner membrane. The transporters are thought to share the same structural fold, which consists of six trans-membrane alpha-helices and three matrix helices, arranged with threefold pseudo-symmetry. During the transport cycle two salt bridge networks on either side of the central cavity might regulate access to a single substrate binding site in an alternating fashion. In the case of proton-substrate symporters, the substrate binding sites contain negatively charged residues that are proposed to be involved in proton transport.
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. 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. 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. A homologue has been identified in the mimivirus genome and shown to be a transporter for dATP and dTTP.
Examples of transported compounds include:
- citrate - SLC25A1
- ornithine - SLC25A2, SLC25A15
- phosphate - SLC25A3, SLC25A23, SLC25A24, SLC25A25
- adenine nucleotide - SLC25A4, SLC25A5, SLC25A6, SLC25A31
- dicarboxylate - SLC25A10
- oxoglutarate - SLC25A11
- glutamate - SLC25A22
Human proteins containing this domain include:
- HDMCP, LOC153328, MCART1, MCART2, MCART6, MTCH1, MTCH2
- UCP1, UCP2, UCP3
- SLC25A1, SLC25A3, SLC25A4, SLC25A5, SLC25A6, SLC25A10, SLC25A11, SLC25A12, SLC25A13, SLC25A14, SLC25A16, SLC25A17, SLC25A18, SLC25A19, SLC25A21, SLC25A22, SLC25A23, SLC25A24, SLC25A25, SLC25A26, SLC25A27, SLC25A28, SLC25A29, SLC25A30, SLC25A31, SLC25A32, SLC25A33, SLC25A34, SLC25A35, SLC25A36, SLC25A37, SLC25A38, SLC25A39, SLC25A40, SLC25A41, SLC25A42, SLC25A43, SLC25A44, SLC25A45, SLC25A46
- Getting a good rate of exchange – the mitochondrial ADP-ATP carrier Article at PDBe
- Transporter Classification Database - Mitochondrial Carrier Superfamily
- Nury H, Dahout-Gonzalez C, Trézéguet V, Lauquin GJ, 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.
- Kuan J, Saier Jr MH (1993). "Expansion of the mitochondrial carrier family". Res. Microbiol. 144 (8): 671–672. doi:10.1016/0923-2508(93)90073-B. PMID 8140286.
- Bamber, Lisa; Harding, Marilyn; Monné, Magnus; Slotboom, Dirk-Jan; Kunji, Edmund R. S. (2007-06-26). "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): 10830–10834. doi:10.1073/pnas.0703969104. ISSN 1091-6490. PMC 1891095. PMID 17566106.
- Bamber, Lisa; Harding, Marilyn; Butler, P. Jonathan G.; Kunji, Edmund R. S. (2006-10-31). "Yeast mitochondrial ADP/ATP carriers are monomeric in detergents". Proceedings of the National Academy of Sciences of the United States of America 103 (44): 16224–16229. doi:10.1073/pnas.0607640103. ISSN 0027-8424. PMC 1618811. PMID 17056710.
- Klingenberg M (1990). "Mechanism and evolution of the uncoupling protein of brown adipose tissue". Trends Biochem. Sci. 15 (3): 108–112. doi:10.1016/0968-0004(90)90194-G. PMID 2158156.
- Lawson JE, Nelson DR, Klingenberg M, Douglas MG (1993). "Site-directed mutagenesis of the yeast mitochondrial ADP/ATP translocator. Six arginines and one lysine are essential". J. Mol. Biol. 230 (4): 1159–1170. doi:10.1006/jmbi.1993.1233. PMID 8487299.
- Jank B, Schweyen RJ, Link TA, Habermann B (1993). "PMP47, a peroxisomal homologue of mitochondrial solute carrier proteins". Trends Biochem. Sci. 18 (11): 427–428. doi:10.1016/0968-0004(93)90141-9. PMID 8291088.
- Monné, Magnus; Palmieri, Ferdinando; Kunji, Edmund R. S. (2013-03-01). "The substrate specificity of mitochondrial carriers: mutagenesis revisited". Molecular Membrane Biology 30 (2): 149–159. doi:10.3109/09687688.2012.737936. ISSN 1464-5203. PMID 23121155.
- Dolce, Vincenza; Cappello, AnnaRita; Capobianco, Loredana (2004-07-18). "Mitochondrial tricarboxylate and dicarboxylate-tricarboxylate carriers: from animals to plants". IUBMB Life 66 (7): 462–71. doi:10.1002/iub.1290. PMID 25045044.
- Palmieri F (1994). "Mitochondrial carrier proteins". FEBS Lett. 346 (1): 48–54. doi:10.1016/0014-5793(94)00329-7. PMID 8206158.
- Walker JE (1992). "The mitochondrial transporter family". Curr. Opin. Struct. Biol. 2 (4): 519–526. doi:10.1016/0959-440X(92)90081-H.
- Palmieri, Ferdinando (2004-02-01). "The mitochondrial transporter family (SLC25): physiological and pathological implications". Pflügers Archiv: European Journal of Physiology 447 (5): 689–709. doi:10.1007/s00424-003-1099-7. ISSN 0031-6768. PMID 14598172.
- Palmieri, Ferdinando; Rieder, Benjamin; Ventrella, Angela; Blanco, Emanuela; Do, Phuc Thi; Nunes-Nesi, Adriano; Trauth, A. Ulrike; Fiermonte, Giuseppe; Tjaden, Joachim (2009-11-06). "Molecular identification and functional characterization of Arabidopsis thaliana mitochondrial and chloroplastic NAD+ carrier proteins". The Journal of Biological Chemistry 284 (45): 31249–31259. doi:10.1074/jbc.M109.041830. ISSN 1083-351X. PMC 2781523. PMID 19745225.
- Palmieri, Ferdinando; Pierri, Ciro Leonardo (2010-01-01). "Mitochondrial metabolite transport". Essays in Biochemistry 47: 37–52. doi:10.1042/bse0470037. ISSN 1744-1358. PMID 20533899.
- Palmieri, Ferdinando (2008-08-01). "Diseases caused by defects of mitochondrial carriers: a review". Biochimica Et Biophysica Acta 1777 (7-8): 564–578. doi:10.1016/j.bbabio.2008.03.008. ISSN 0006-3002. PMID 18406340.
- Gutiérrez-Aguilar, Manuel; Baines, Christopher P. (2013-09-15). "Physiological and pathological roles of mitochondrial SLC25 carriers". The Biochemical Journal 454 (3): 371–386. doi:10.1042/BJ20121753. ISSN 1470-8728. PMC 3806213. PMID 23988125.
- Palmieri, Ferdinando (2013-06-01). "The mitochondrial transporter family SLC25: identification, properties and physiopathology". Molecular Aspects of Medicine 34 (2-3): 465–484. doi:10.1016/j.mam.2012.05.005. ISSN 1872-9452. PMID 23266187.
- Kuan, J.; Saier, M. H. (1993-01-01). "The mitochondrial carrier family of transport proteins: structural, functional, and evolutionary relationships". Critical Reviews in Biochemistry and Molecular Biology 28 (3): 209–233. doi:10.3109/10409239309086795. ISSN 1040-9238. PMID 8325039.
- 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.
- Ryan MT, Müller H, Pfanner N (July 1999). "Functional staging of ADP/ATP carrier translocation across the outer mitochondrial membrane". J. Biol. Chem. 274 (29): 20619–27. doi:10.1074/jbc.274.29.20619. PMID 10400693.
- Falconi M, Chillemi G, Di Marino D, D'Annessa I, Morozzo della Rocca B, Palmieri L, Desideri A (November 2006). "Structural dynamics of the mitochondrial ADP/ATP carrier revealed by molecular dynamics simulation studies". Proteins 65 (3): 681–91. doi:10.1002/prot.21102. PMID 16988954.
- Robinson, Alan J.; Overy, Catherine; Kunji, Edmund R. S. (2008-11-18). "The mechanism of transport by mitochondrial carriers based on analysis of symmetry". Proceedings of the National Academy of Sciences 105 (46): 17766–17771. doi:10.1073/pnas.0809580105. ISSN 0027-8424. PMC 2582046. PMID 19001266.
- Kunji, Edmund R. S.; Robinson, Alan J. (2010-08-01). "Coupling of proton and substrate translocation in the transport cycle of mitochondrial carriers". Current Opinion in Structural Biology 20 (4): 440–447. doi:10.1016/j.sbi.2010.06.004. ISSN 1879-033X. PMID 20598524.
- Kunji, Edmund R. S.; Robinson, Alan J. (2006-10-01). "The conserved substrate binding site of mitochondrial carriers". Biochimica Et Biophysica Acta 1757 (9-10): 1237–1248. doi:10.1016/j.bbabio.2006.03.021. ISSN 0006-3002. PMID 16759636.
- Cappello, Anna Rita; Curcio, Rosita; Valeria Miniero, Daniela; Stipani, Italo; Robinson, Alan J.; Kunji, Edmund R. S.; Palmieri, Ferdinando (2006-10-13). "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. doi:10.1016/j.jmb.2006.08.041. ISSN 0022-2836. PMID 16962611.
- Cappello, Anna R.; Miniero, Daniela V.; Curcio, Rosita; Ludovico, Anna; Daddabbo, Lucia; Stipani, Italo; Robinson, Alan J.; Kunji, Edmund R. S.; Palmieri, Ferdinando (2007-06-01). "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): 400–412. doi:10.1016/j.jmb.2007.03.048. ISSN 0022-2836. PMID 17442340.
- Zara, Vincenzo; Ferramosca, Alessandra; Capobianco, Loredana; Baltz, Katrin M.; Randel, Olga; Rassow, Joachim; Palmieri, Ferdinando; Papatheodorou, Panagiotis (2007-12-01). "Biogenesis of yeast dicarboxylate carrier: the carrier signature facilitates translocation across the mitochondrial outer membrane". Journal of Cell Science 120 (Pt 23): 4099–4106. doi:10.1242/jcs.018929. ISSN 0021-9533. PMID 18032784.
- Monné, Magnus; Robinson, Alan J.; Boes, Christoph; Harbour, Michael E.; Fearnley, Ian M.; Kunji, Edmund R. S. (2007-04-01). "The mimivirus genome encodes a mitochondrial carrier that transports dATP and dTTP". Journal of Virology 81 (7): 3181–3186. doi:10.1128/JVI.02386-06. ISSN 0022-538X. PMC 1866048. PMID 17229695.
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
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Internal database links
|SCOOP:||HMD DUF3764 PrcB_C Fuseless|
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.
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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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, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
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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.
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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.
|Number in seed:||161|
|Number in full:||47534|
|Average length of the domain:||94.40 aa|
|Average identity of full alignment:||21 %|
|Average coverage of the sequence by the domain:||74.17 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||24|
|Download:||download the raw HMM for this family|
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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 More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
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There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
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Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
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There is 1 interaction for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 30 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 seqence.
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