Biology:SLC25A3

Generic protein structure example

Phosphate carrier protein, mitochondrial is a protein that in humans is encoded by the SLC25A3 gene. 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. There are two significant isoforms of this gene expressed in human cells, which differ slightly in structure and function. 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.

Structure

The SLC25A3 gene is located on the q arm of chromosome 12 in position 23.1 and spans 8,376 base pairs. The gene has 9 exons and produces a 40.1 kDa protein composed of 362 amino acids. 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. 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. There exist two transcript variants of this protein, PHC-A and PHC-B, which differ by 13 amino acids. Isoform A contains 42 amino acids while Isoform B contains 41. In vitro, the isoforms differ in their substrate affinities and transport rates.

Function

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. In the final steps of oxidative phosphorylation, this protein catalyzes the uptake of a phosphate ion with a proton across the mitochondrial inner membrane. The availability of inorganic phosphate for oxidative phosphorylation is mainly dependent on PHC activity. To substantially affect oxidative phosphorylation, PHC depletion must be severe, exceeding 85%. This protein may be involved in regulation of the mitochondrial permeability transition pore (mPTP).

Clinical significance

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.

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.

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.

Interactions

The encoded protein interacts with PPIF; this interaction is impaired by CsA.

See also

• Solute carrier family

Further reading

• "Nucleotide sequence of a human heart cDNA encoding the mitochondrial phosphate carrier". DNA Sequence 2 (2): 133–5. 1992. doi:10.3109/10425179109039683. PMID 1777677. 
• "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1-2): 171–4. January 1994. doi:10.1016/0378-1119(94)90802-8. PMID 8125298. 
• "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. April 1994. PMID 8144629. 
• "Chromosomal localization of the mitochondrial phosphate carrier gene PHC to 12q23". Genomics 29 (3): 814–5. October 1995. doi:10.1006/geno.1995.9924. PMID 8575787. 
• "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1-2): 149–56. October 1997. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149. 
• "Human mitochondrial transmembrane metabolite carriers: tissue distribution and its implication for mitochondrial disorders". Journal of Bioenergetics and Biomembranes 30 (3): 277–84. June 1998. doi:10.1023/A:1020501021222. PMID 9733094. 
• "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology 6 (2): 97–105. February 2004. doi:10.1038/ncb1086. PMID 14743216. 
• "Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization". Current Biology 14 (16): 1436–50. August 2004. doi:10.1016/j.cub.2004.07.051. PMID 15324660. 
• "Functional analysis of the promoter of the mitochondrial phosphate carrier human gene: identification of activator and repressor elements and their transcription factors". The Biochemical Journal 391 (Pt 3): 613–21. November 2005. doi:10.1042/BJ20050776. PMID 15984930. 
• "Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries". DNA Research 12 (2): 117–26. 2007. doi:10.1093/dnares/12.2.117. PMID 16303743. 
• "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation". American Journal of Human Genetics 80 (3): 478–84. March 2007. doi:10.1086/511788. PMID 17273968. 

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