Tricarboxylate transport protein, mitochondrial
SLC25A1 | |||
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Identifiers | |||
Gene ontology | |||
Molecular function | |||
Cellular component | |||
Biological process | |||
Sources:Amigo / QuickGO |
Ensembl | |||||||||
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UniProt | |||||||||
RefSeq (mRNA) | |||||||||
RefSeq (protein) |
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Location (UCSC) | Chr 22: 19.18 – 19.18 Mb | Chr 16: 17.74 – 17.75 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Tricarboxylate transport protein, mitochondrial, also known as tricarboxylate carrier protein and citrate transport protein (CTP), is a protein that in humans is encoded by the SLC25A1 gene.[5][6][7][8] SLC25A1 belongs to the mitochondrial carrier gene family SLC25.[9][10][11] High levels of the tricarboxylate transport protein are found in the liver, pancreas and kidney. Lower or no levels are present in the brain, heart, skeletal muscle, placenta and lung.[9][11]
The tricarboxylate transport protein is located within the inner mitochondria membrane. It provides a link between the mitochondrial matrix and cytosol by transporting
Structure
The structure of the tricarboxylate transport protein is consistent with the structures of other mitochondrial carriers.[9][10][12] In particular, the tricarboxylate transport protein has a tripartite structure consisting of three repeated domains that are approximately 100 amino acids in length.[9][12] Each repeat forms a transmembrane domain consisting of two hydrophobic α-helices.[9][10][15] The amino and carboxy termini are located on the cytosolic side of the inner mitochondrial membrane.[9][10] Each domain is linked by two hydrophilic loops located on the cytosolic side of the membrane.[9][10][15][16] The two α-helices of each repeated domain are connected by hydrophilic loops located on the matrix side of the membrane.[9][10][16] A salt bridge network is present on both the matrix side and cytoplasmic side of the tricarboxylate transport protein.[16]
Transport mechanism
The tricarboxylate transport protein exists in two states: a cytoplasmic state where it accepts malate from the cytoplasm and a matrix state where it accepts citrate from the mitochondrial matrix.[17] A single binding site is present near the center of the cavity of the tricarboxylate transport protein, which can be either exposed to the cytosol or the mitochondrial matrix depending on the state.[15][16][17] A substrate induced conformational change occurs when citrate enters from the matrix side and binds to the central cavity of the tricarboxylate transport protein.[9] This conformational change opens a gate on the cytosolic side and closes the gate on the matrix side.[9] Likewise, when malate enters from the cytosolic side, the matrix gate opens and the cytosolic gate closes.[9] Each side of the transporter is open and closed by the disruption and formation of the salt bridge networks, which allows access to the single binding site.[15][16][17][18][19]
Disease relevance
Mutations in this gene have been associated with the inborn error of metabolism combined D-2- and L-2-hydroxyglutaric aciduria,[20] which was the first reported case of a pathogenic mutation of the SLC25A1 gene.[16][21] Patients with D-2/L-2-hydroxyglutaric aciduria display neonatal onset metabolic encephalopathy, infantile epilepsy, global developmental delay, muscular hypotonia and early death.[16][21][22] It is believed low levels of citrate in the cytosol and high levels of citrate in the mitochondria caused by the impaired citrate transport plays a role in the disease.[16][22] In addition, increased expression of the tricarboxylate transport protein has been linked to cancer[11][23][24] and the production of inflammatory mediators.[25][26][27] Therefore, it has been suggested that inhibition of the tricarboxylate transport protein may have a therapeutic effect in chronic inflammation diseases and cancer.[26]
See also
- SLC25A1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000100075 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000003528 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 8666394.
- PMID 9254007.
- PMID 25045044.
- ^ "Entrez Gene: SLC25A1 solute carrier family 25 (mitochondrial carrier; citrate transporter), member 1".
- ^ PMID 23266187.
- ^ S2CID 25304722.
- ^ PMID 24832661.
- ^ ISBN 978-1-4641-2610-9.
- ISBN 978-1-118-91840-1.
- ISBN 978-1-4641-2611-6.
- ^ PMID 26453935.
- ^ PMID 29031613.
- ^ PMID 16469842.
- PMID 19001266.
- PMID 16759636.
- PMID 23561848.
- ^ ISBN 978-3-662-49771-5.
- ^ S2CID 6953669.
- PMID 27856334.
- PMID 29546056.
- PMID 21787310.
- ^ PMID 25072865.
- PMID 25917893.
Further reading
- Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. PMID 17353931.
- Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. S2CID 4427026.
- Gong W, Emanuel BS, Collins J, Kim DH, Wang Z, Chen F, Zhang G, Roe B, Budarf ML (June 1996). "A transcription map of the DiGeorge and velo-cardio-facial syndrome minimal critical region on 22q11". Human Molecular Genetics. 5 (6): 789–800. PMID 8776594.
- Goldmuntz E, Wang Z, Roe BA, Budarf ML (April 1996). "Cloning, genomic organization, and chromosomal localization of human citrate transport protein to the DiGeorge/velocardiofacial syndrome minimal critical region". Genomics. 33 (2): 271–6. PMID 8660975.
- Bonofiglio D, Santoro A, Martello E, Vizza D, Rovito D, Cappello AR, Barone I, Giordano C, Panza S, Catalano S, Iacobazzi V, Dolce V, Andò S (June 2013). "Mechanisms of divergent effects of activated peroxisome proliferator-activated receptor-γ on mitochondrial citrate carrier expression in 3T3-L1 fibroblasts and mature adipocytes". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1831 (6): 1027–36. PMID 23370576.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.