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Link to original content: http://wikipedia.org/wiki/SLC25A3
Phosphate carrier protein, mitochondrial - Wikipedia Jump to content

Phosphate carrier protein, mitochondrial

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SLC25A3
Identifiers
AliasesSLC25A3, PHC, PTP, OK/SW-cl.48, solute carrier family 25 member 3
External IDsOMIM: 600370; MGI: 1353498; HomoloGene: 37649; GeneCards: SLC25A3; OMA:SLC25A3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5250

18674

Ensembl

ENSG00000075415

ENSMUSG00000061904

UniProt

Q00325

Q8VEM8

RefSeq (mRNA)

NM_213612
NM_002635
NM_005888
NM_213611

NM_133668

RefSeq (protein)

NP_002626
NP_005879
NP_998776
NP_005879.1

NP_598429

Location (UCSC)Chr 12: 98.59 – 98.61 MbChr 10: 90.95 – 90.96 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Phosphate carrier protein, mitochondrial is a protein that in humans is encoded by the SLC25A3 gene.[5][6] The encoded protein is a transmembrane protein located in the mitochondrial inner membrane and catalyzes the transport of phosphate ions across it for the purpose of oxidative phosphorylation.[7][8] There are two significant isoforms of this gene expressed in human cells, which differ slightly in structure and function.[9] Mutations in this gene can cause mitochondrial phosphate carrier deficiency (MPCD), a fatal disorder of oxidative phosphorylation symptomized by lactic acidosis, neonatal hypotonia, hypertrophic cardiomyopathy, and death within the first year of life.[7][8]

Structure

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The SLC25A3 gene is located on the q arm of chromosome 12 in position 23.1 and spans 8,376 base pairs.[6] The gene has 9 exons and produces a 40.1 kDa protein composed of 362 amino acids.[10][11][9] The encoded protein (PHC) is a multi-pass transmembrane protein located in the mitochondrial inner membrane; it contains six transmembrane segments, emerging into a large extramembranous loop.[7][8][12] Both the N-terminal and C-terminal regions of this protein protrude toward the cytosol. PHC contains three related segments arranged in tandem which are related to those found in other characterized members of the mitochondrial carrier family.[6] There exist two transcript variants of this protein, PHC-A and PHC-B, which differ by 13 amino acids.[12] Isoform A contains 42 amino acids while Isoform B contains 41. In vitro, the isoforms differ in their substrate affinities and transport rates.[13][9]

Function

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The encoded protein (PHC) catalyzes the transport of phosphate from the cytosol into the mitochondrial matrix, either by proton cotransport or in exchange for hydroxyl ions.[6] In the final steps of oxidative phosphorylation, this protein catalyzes the uptake of a phosphate ion with a proton across the mitochondrial inner membrane.[9] The availability of inorganic phosphate for oxidative phosphorylation is mainly dependent on PHC activity.[13] To substantially affect oxidative phosphorylation, PHC depletion must be severe, exceeding 85%.[14] This protein may be involved in regulation of the mitochondrial permeability transition pore (mPTP).[7][8]

Clinical significance

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Mutations in this gene can cause mitochondrial phosphate carrier deficiency (MPCD), a fatal disorder of oxidative phosphorylation. Symptoms include lactic acidosis, hypertrophic cardiomyopathy, and neonatal hypotonia; afflicted patients die within the first year of life.[7][8]

Isoform A of this gene is expressed at high levels in heart, pancreatic, and skeletal muscle cells while Isoform B is expressed in all tissues, albeit poorly.[13][9]

In the sole recorded case of a mutation in this gene, a homozygous mutation (c.215G>A) in the alternatively spliced exon 3A of this gene caused an amino acid replacement (G72E) in Isoform A. This leads to ATP synthase deficiency in muscle cells, which express Isoform A, but not in fibroblasts, which express Isoform B, causing MPCD and the aforementioned standard symptoms.[15][9]

Interactions

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The encoded protein interacts with PPIF; this interaction is impaired by CsA.[7][8]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000075415 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000061904 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Jabs EW, Thomas PJ, Bernstein M, Coss C, Ferreira GC, Pedersen PL (May 1994). "Chromosomal localization of genes required for the terminal steps of oxidative metabolism: alpha and gamma subunits of ATP synthase and the phosphate carrier". Human Genetics. 93 (5): 600–2. doi:10.1007/bf00202832. PMID 8168843. S2CID 39597611.
  6. ^ a b c d "Entrez Gene: SLC25A3 solute carrier family 25 (mitochondrial carrier; phosphate carrier), member 3".Public Domain This article incorporates text from this source, which is in the public domain.
  7. ^ a b c d e f "SLC25A3 - Phosphate carrier protein, mitochondrial precursor - Homo sapiens (Human) - SLC25A46 gene & protein". www.uniprot.org. Retrieved 2018-08-20. This article incorporates text available under the CC BY 4.0 license.
  8. ^ a b c d e f "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
  9. ^ a b c d e f Online Mendelian Inheritance in Man (OMIM): SLC25A3 - 600370
  10. ^ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
  11. ^ "SLC25A3 - Phosphate carrier protein, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  12. ^ a b Dolce V, Iacobazzi V, Palmieri F, Walker JE (April 1994). "The sequences of human and bovine genes of the phosphate carrier from mitochondria contain evidence of alternatively spliced forms". The Journal of Biological Chemistry. 269 (14): 10451–60. doi:10.1016/S0021-9258(17)34081-4. PMID 8144629.
  13. ^ a b c Huizing M, Ruitenbeek W, van den Heuvel LP, Dolce V, Iacobazzi V, Smeitink JA, Palmieri F, Trijbels JM (June 1998). "Human mitochondrial transmembrane metabolite carriers: tissue distribution and its implication for mitochondrial disorders". Journal of Bioenergetics and Biomembranes. 30 (3): 277–84. doi:10.1023/A:1020501021222. PMID 9733094. S2CID 45811751.
  14. ^ Seifert EL, Gál A, Acoba MG, Li Q, Anderson-Pullinger L, Golenár T, Moffat C, Sondheimer N, Claypool SM, Hajnóczky G (December 2016). "Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION". The Journal of Biological Chemistry. 291 (50): 26126–26137. doi:10.1074/jbc.M116.744714. PMC 5207081. PMID 27780865.
  15. ^ Mayr JA, Merkel O, Kohlwein SD, Gebhardt BR, Böhles H, Fötschl U, Koch J, Jaksch M, Lochmüller H, Horváth R, Freisinger P, Sperl W (March 2007). "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation". American Journal of Human Genetics. 80 (3): 478–84. doi:10.1086/511788. PMC 1821108. PMID 17273968.

Further reading

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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