Summary: Mitochondrial carrier protein
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Mitochondrial carrier Edit Wikipedia article
Mitochondrial ADP/ATP carrier
|SCOPe||1okc / SUPFAM|
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 GutiÃ©rrez-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 Î±-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. 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 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.
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 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.
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 / , the yeast ADP/ATP carrier Aac2p / , the yeast ADP/ATP carrier Aac3p / , 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 . In addition, there are structures of the calcium regulatory domains of the mitochondrial ATP-Mg/Pi carrier in the calcium-bound state /  and mitochondrial aspartate/glutamate carriers in different regulatory states / / .
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.
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 â€“ SLC25A1
- ornithine â€“ SLC25A2, SLC25A15
- phosphate â€“ SLC25A3, SLC25A23, SLC25A24, SLC25A25
- adenine nucleotide â€“ SLC25A4, SLC25A5, SLC25A6, SLC25A31
- dicarboxylate â€“ SLC25A10
- oxoglutarate â€“ SLC25A11
- glutamate â€“ 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
- Nury, H.; Dahout-Gonzalez, C.; TrÃ©zÃ©guet, 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: 713â€“41. doi:10.1146/annurev.biochem.75.103004.142747. PMID 16756509.
- Kuan J, Saier MH (October 1993). "Expansion of the mitochondrial carrier family". Research in Microbiology. 144 (8): 671â€“2. doi:10.1016/0923-2508(93)90073-B. PMID 8140286.
- Bamber L, Harding M, MonnÃ© 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): 10830â€“4. Bibcode:2007PNAS..10410830B. doi:10.1073/pnas.0703969104. PMC 1891095. PMID 17566106.
- 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): 16224â€“9. Bibcode:2006PNAS..10316224B. doi:10.1073/pnas.0607640103. PMC 1618811. PMID 17056710.
- Klingenberg M (March 1990). "Mechanism and evolution of the uncoupling protein of brown adipose tissue". Trends in Biochemical Sciences. 15 (3): 108â€“12. doi:10.1016/0968-0004(90)90194-G. PMID 2158156.
- 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): 1159â€“70. doi:10.1006/jmbi.1993.1233. PMID 8487299.
- 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): 427â€“8. doi:10.1016/0968-0004(93)90141-9. PMID 8291088.
- MonnÃ© M, Palmieri F, Kunji ER (March 2013). "The substrate specificity of mitochondrial carriers: mutagenesis revisited". Molecular Membrane Biology. 30 (2): 149â€“59. doi:10.3109/09687688.2012.737936. PMID 23121155.
- Dolce V, Cappello AR, Capobianco L (July 2014). "Mitochondrial tricarboxylate and dicarboxylate-tricarboxylate carriers: from animals to plants". IUBMB Life. 66 (7): 462â€“71. doi:10.1002/iub.1290. PMID 25045044.
- Palmieri F (June 1994). "Mitochondrial carrier proteins". FEBS Letters. 346 (1): 48â€“54. doi:10.1016/0014-5793(94)00329-7. PMID 8206158.
- Walker JE (1992). "The mitochondrial transporter family". Curr. Opin. Struct. Biol. 2 (4): 519â€“526. doi:10.1016/0959-440X(92)90081-H.
- Palmieri F (February 2004). "The mitochondrial transporter family (SLC25): physiological and pathological implications". PflÃ¼gers Archiv. 447 (5): 689â€“709. doi:10.1007/s00424-003-1099-7. PMID 14598172.
- 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): 31249â€“59. doi:10.1074/jbc.M109.041830. PMC 2781523. PMID 19745225.
- Palmieri F, Pierri CL (2010-01-01). "Mitochondrial metabolite transport". Essays in Biochemistry. 47: 37â€“52. doi:10.1042/bse0470037. PMID 20533899.
- Palmieri F (2008-08-01). "Diseases caused by defects of mitochondrial carriers: a review". Biochimica et Biophysica Acta. 1777 (7â€“8): 564â€“78. doi:10.1016/j.bbabio.2008.03.008. PMID 18406340.
- GutiÃ©rrez-Aguilar M, Baines CP (September 2013). "Physiological and pathological roles of mitochondrial SLC25 carriers". The Biochemical Journal. 454 (3): 371â€“86. doi:10.1042/BJ20121753. PMC 3806213. PMID 23988125.
- Palmieri F (2013-06-01). "The mitochondrial transporter family SLC25: identification, properties and physiopathology". Molecular Aspects of Medicine. 34 (2â€“3): 465â€“84. doi:10.1016/j.mam.2012.05.005. PMID 23266187.
- 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): 209â€“33. doi:10.3109/10409239309086795. PMID 8325039.
- 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. 1863 (10): 2379â€“2393. doi:10.1016/j.bbamcr.2016.03.015. ISSN 0006-3002. PMID 27001633.
- Ryan MT, MÃ¼ller H, Pfanner N (July 1999). "Functional staging of ADP/ATP carrier translocation across the outer mitochondrial membrane". The Journal of Biological Chemistry. 274 (29): 20619â€“27. doi:10.1074/jbc.274.29.20619. PMID 10400693.
- 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): 17766â€“71. Bibcode:2008PNAS..10517766R. doi:10.1073/pnas.0809580105. PMC 2582046. PMID 19001266.
- Pebay-Peyroula, Eva; Dahout-Gonzalez, CÃ©cile; Kahn, Richard; TrÃ©zÃ©guet, VÃ©ronique; Lauquin, Guy J.-M.; Brandolin, GÃ©rard (2003). "Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside". Nature. 426 (6962): 39â€“44. Bibcode:2003Natur.426...39P. doi:10.1038/nature02056. ISSN 1476-4687. PMID 14603310.
- Nury, H.; Dahout-Gonzalez, C.; TrÃ©zÃ©guet, 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): 6031â€“6036. doi:10.1016/j.febslet.2005.09.061. ISSN 0014-5793. PMID 16226253.
- 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): E426â€“434. Bibcode:2014PNAS..111E.426R. doi:10.1073/pnas.1320692111. ISSN 1091-6490. PMC 3910652. PMID 24474793.
- Ruprecht, Jonathan J.; King, Martin S.; ZÃ¶gg, 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): 435â€“447.e15. doi:10.1016/j.cell.2018.11.025. ISSN 1097-4172. PMC 6349463. PMID 30611538.
- 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. 1847 (10): 1245â€“1253. doi:10.1016/j.bbabio.2015.07.002. ISSN 0006-3002. PMC 4562336. PMID 26164100.
- Yang, Qin; BrÃ¼schweiler, Sven; Chou, James J. (2014). "A self-sequestered calmodulin-like CaÂ²âº sensor of mitochondrial SCaMC carrier and its implication to CaÂ²âº-dependent ATP-Mg/P(i) transport". Structure. 22 (2): 209â€“217. doi:10.1016/j.str.2013.10.018. ISSN 1878-4186. PMC 3946054. PMID 24332718.
- 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. Bibcode:2014NatCo...5.5491T. doi:10.1038/ncomms6491. ISSN 2041-1723. PMC 4250520. PMID 25410934.
- Kunji ER, Robinson AJ (August 2010). "Coupling of proton and substrate translocation in the transport cycle of mitochondrial carriers". Current Opinion in Structural Biology. 20 (4): 440â€“7. doi:10.1016/j.sbi.2010.06.004. PMID 20598524.
- Kunji ER, Robinson AJ (2006-10-01). "The conserved substrate binding site of mitochondrial carriers". Biochimica et Biophysica Acta. 1757 (9â€“10): 1237â€“48. doi:10.1016/j.bbabio.2006.03.021. PMID 16759636.
- Cappello AR, Curcio R, Valeria Miniero D, Stipani I, Robinson AJ, Kunji ER, Palmieri F (October 2006). "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): 51â€“62. doi:10.1016/j.jmb.2006.08.041. PMID 16962611.
- Cappello AR, Miniero DV, Curcio R, Ludovico A, Daddabbo L, Stipani I, Robinson AJ, Kunji ER, Palmieri F (June 2007). "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): 400â€“12. doi:10.1016/j.jmb.2007.03.048. PMID 17442340.
- Zara V, Ferramosca A, Capobianco L, Baltz KM, Randel O, Rassow J, Palmieri F, Papatheodorou P (December 2007). "Biogenesis of yeast dicarboxylate carrier: the carrier signature facilitates translocation across the mitochondrial outer membrane". Journal of Cell Science. 120 (Pt 23): 4099â€“106. doi:10.1242/jcs.018929. PMID 18032784.
- MonnÃ© M, Robinson AJ, Boes C, Harbour ME, Fearnley IM, Kunji ER (April 2007). "The mimivirus genome encodes a mitochondrial carrier that transports dATP and dTTP". Journal of Virology. 81 (7): 3181â€“6. doi:10.1128/JVI.02386-06. 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.
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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.
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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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|Number in seed:||160|
|Number in full:||193024|
|Average length of the domain:||94.20 aa|
|Average identity of full alignment:||21 %|
|Average coverage of the sequence by the domain:||71.39 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||29|
|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....
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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:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
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.
Loading structure mapping...