Calcium-binding mitochondrial carrier protein Aralar1

Calcium-binding mitochondrial carrier protein Aralar1 is a protein that in humans is encoded by the SLC25A12 gene.[5][6][7][8] Aralar is an integral membrane protein located in the inner mitochondrial membrane. Its primary function as an antiporter is the transport of cytoplasmic glutamate with mitochondrial aspartate across the inner mitochondrial membrane, dependent on the binding of one calcium ion. Mutations in this gene cause early infantile epileptic encephalopathy 39 (EIEE39), symptomized by global hypomyelination of the central nervous system, refractory seizures, and neurodevelopmental impairment.[9][10] This gene has connections to autism.[11][12]

SLC25A12
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4P60, 4P5X,%%s4P5X, 4P60
Identifiers
Aliases	SLC25A12, AGC1, ARALAR, solute carrier family 25 member 12, EIEE39
External IDs	OMIM: 603667 MGI: 1926080 HomoloGene: 48235 GeneCards: SLC25A12
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q31.1 Start 171,783,405 bp[1] End 171,999,859 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2|2 C2 Start 71,271,063 bp[2] End 71,367,749 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • calcium ion binding • metal ion binding • L-aspartate transmembrane transporter activity • L-glutamate transmembrane transporter activity • acidic amino acid transmembrane transporter activity • GO:0022891 transmembrane transporter activity • identical protein binding Cellular component • membrane • myelin • mitochondrion • mitochondrial inner membrane • integral component of membrane Biological process • gluconeogenesis • malate-aspartate shuttle • response to calcium ion • transmembrane transport • aspartate transport • L-glutamate transport • transport • glutamate biosynthetic process • positive regulation of glucose metabolic process • positive regulation of myelination • L-aspartate transport • negative regulation of glucose catabolic process to lactate via pyruvate • positive regulation of ATP biosynthetic process • mitochondrial calcium ion transmembrane transport Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	8604	78830
Ensembl	ENSG00000115840	ENSMUSG00000027010
UniProt	O75746	Q8BH59
RefSeq (mRNA)	NM_003705	NM_172436
RefSeq (protein)	NP_003696	NP_766024
Location (UCSC)	Chr 2: 171.78 – 172 Mb	Chr 2: 71.27 – 71.37 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

The SLC25A12 gene is located on the q arm of chromosome 2 in position 31.1 and spans 110,902 base pairs.[8] The gene produces a 74.8 kDa protein composed of 678 amino acids.[13][14] The encoded protein, Aralar1, is a multi-pass membrane protein located in the inner mitochondrial membrane.[9][10] The N-terminal half of this protein contains 2 imperfect EF-hand domains along with 3 canonical EF-hand calcium-binding domains; this part of the protein binds calcium in vitro. Aralar's C-terminal half shares 28-29% identity with other members of the mitochondrial solute carrier family, including SLC25A11, SLC25A5, SLC25A1, and has 6 putative transmembrane domains like the other members of mitochondrial solute carrier family.[15][16]

Function

The protein encoded by SLC25A12, Aralar1, is a mitochondrial calcium-binding carrier that facilitates the calcium-dependent exchange of cytoplasmic glutamate with mitochondrial aspartate across the mitochondrial inner membrane. Aralar binds to one calcium ion with high affinity. Upon calcium binding, the EF-hand-containing regulatory N-terminal domain binds to the C-terminal domain, opening a vestibule which allows the substrates to be translocated through the carrier domain. In the absence of calcium, the linker loop domain may close the vestibule, which may prevent substrates from entering the carrier domain.[17] As a member of the malate-aspartate NADH shuttle, Aralar is also involved in the transfer of cytosolic reducing equivalents from the cytosol to the mitochondrial matrix.[18] Aralar, along with the protein encoded by SLC25A13, are both calcium-binding aspartate/glutamate carriers which are substrates in the TIMM8A/TIMM13 complex.

Clinical Significance

Overexpression of Aralar1 augments mitochondrial metabolism and increases insulin secretion in pancreatic cells.[19] Aralar is expressed as both a 3.2 kb and 2.9 kb mRNA transcript in heart and skeletal muscle cells, and in lesser amounts in brain and kidney cells.[15][16]

Epileptic Encephalopathy

Mutations in the SLC25A12 gene cause early infantile epileptic encephalopathy 39(EIEE39), characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE39 is characterized by global hypomyelination of the central nervous system, with the gray matter appearing relatively unaffected. Inheritance is autosomal recessive.[9][10]

Autism

2 SNPs in introns 3 and 16 of the SLC25A12 gene may be associated with autism.[11] In Brodmann's Area (BA) 46 of the prefrontal cortex, SLC25A12 is expressed more strongly in the neurons of autistic people. SLC25A12 overexpression may modify neuronal networks in certain subregions of the brain during the fetal development of autistic patients.[12]

Interactions

Aralar has interactions with SCO1, ATF2, COX14, COA3, in addition to 36 other proteins.[20]

See also

• Solute carrier family

References

1. GRCh38: Ensembl release 89: ENSG00000115840 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000027010 - 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. del Arco A, Satrústegui J (September 1998). "Molecular cloning of Aralar, a new member of the mitochondrial carrier superfamily that binds calcium and is present in human muscle and brain". The Journal of Biological Chemistry. 273 (36): 23327–34. doi:10.1074/jbc.273.36.23327. PMID 9722566.
6. Crackower MA, Sinasac DS, Lee JR, Herbrick JA, Tsui LC, Scherer SW (Apr 2000). "Assignment of the SLC25A12 gene coding for the human calcium-binding mitochondrial solute carrier protein aralar to human chromosome 2q24". Cytogenetics and Cell Genetics. 87 (3–4): 197–8. doi:10.1159/000015465. PMID 10702666.
7. Palmieri L, Pardo B, Lasorsa FM, del Arco A, Kobayashi K, Iijima M, Runswick MJ, Walker JE, Saheki T, Satrústegui J, Palmieri F (September 2001). "Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria". The EMBO Journal. 20 (18): 5060–9. doi:10.1093/emboj/20.18.5060. PMC 125626. PMID 11566871.
8. "Entrez Gene: SLC25A12 solute carrier family 25 (mitochondrial carrier, Aralar), member 12". This article incorporates text from this source, which is in the public domain.
9. "SLC25A12 - Calcium-binding mitochondrial carrier protein Aralar1 - Homo sapiens (Human) - SLC25A12 gene & protein". www.uniprot.org. Retrieved 2018-08-22. This article incorporates text available under the CC BY 4.0 license.
10. "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
11. Segurado R, Conroy J, Meally E, Fitzgerald M, Gill M, Gallagher L (November 2005). "Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31". The American Journal of Psychiatry. 162 (11): 2182–4. doi:10.1176/appi.ajp.162.11.2182. hdl:2262/34993. PMID 16263864.
12. Lepagnol-Bestel AM, Maussion G, Boda B, Cardona A, Iwayama Y, Delezoide AL, Moalic JM, Muller D, Dean B, Yoshikawa T, Gorwood P, Buxbaum JD, Ramoz N, Simonneau M (April 2008). "SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects". Molecular Psychiatry. 13 (4): 385–97. doi:10.1038/sj.mp.4002120. PMID 18180767.
13. 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.
14. "SLC25A12 - Calcium-binding mitochondrial carrier protein Aralar1". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 2018-08-25. Retrieved 2018-08-24.
15. del Arco A, Satrústegui J (September 1998). "Molecular cloning of Aralar, a new member of the mitochondrial carrier superfamily that binds calcium and is present in human muscle and brain". The Journal of Biological Chemistry. 273 (36): 23327–34. doi:10.1074/jbc.273.36.23327. PMID 9722566.
16. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: {603667}: {08/01/2016}: . World Wide Web URL: https://omim.org/
17. Thangaratnarajah C, Ruprecht JJ, Kunji ER (November 2014). "Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers". Nature Communications. 5: 5491. doi:10.1038/ncomms6491. PMC 4250520. PMID 25410934.
18. Jalil MA, Begum L, Contreras L, Pardo B, Iijima M, Li MX, Ramos M, Marmol P, Horiuchi M, Shimotsu K, Nakagawa S, Okubo A, Sameshima M, Isashiki Y, Del Arco A, Kobayashi K, Satrústegui J, Saheki T (September 2005). "Reduced N-acetylaspartate levels in mice lacking aralar, a brain- and muscle-type mitochondrial aspartate-glutamate carrier". The Journal of Biological Chemistry. 280 (35): 31333–9. doi:10.1074/jbc.M505286200. PMID 15987682.
19. Rubi B, del Arco A, Bartley C, Satrustegui J, Maechler P (December 2004). "The malate-aspartate NADH shuttle member Aralar1 determines glucose metabolic fate, mitochondrial activity, and insulin secretion in beta cells". The Journal of Biological Chemistry. 279 (53): 55659–66. doi:10.1074/jbc.M409303200. PMID 15494407.
20. IntAct. "SLC25A12 interactions". www.ebi.ac.uk. Retrieved 2018-08-23.

Further reading

• Kobayashi K, Sinasac DS, Iijima M, Boright AP, Begum L, Lee JR, Yasuda T, Ikeda S, Hirano R, Terazono H, Crackower MA, Kondo I, Tsui LC, Scherer SW, Saheki T (June 1999). "The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein". Nature Genetics. 22 (2): 159–63. doi:10.1038/9667. PMID 10369257.
• Sanz R, del Arco A, Ayuso C, Ramos C, Satrústegui J (2000). "Assignment of the calcium-binding mitochondrial carrier Aralar1 gene (SLC25A12) to human chromosome band 2q31 by in situ hybridization". Cytogenetics and Cell Genetics. 89 (3–4): 143–4. doi:10.1159/000015595. PMID 10965105.
• Ramoz N, Reichert JG, Smith CJ, Silverman JM, Bespalova IN, Davis KL, Buxbaum JD (April 2004). "Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism". The American Journal of Psychiatry. 161 (4): 662–9. doi:10.1176/appi.ajp.161.4.662. PMID 15056512.
• Rubi B, del Arco A, Bartley C, Satrustegui J, Maechler P (December 2004). "The malate-aspartate NADH shuttle member Aralar1 determines glucose metabolic fate, mitochondrial activity, and insulin secretion in beta cells". The Journal of Biological Chemistry. 279 (53): 55659–66. doi:10.1074/jbc.M409303200. PMID 15494407.
• Rabionet R, McCauley JL, Jaworski JM, Ashley-Koch AE, Martin ER, Sutcliffe JS, Haines JL, DeLong GR, Abramson RK, Wright HH, Cuccaro ML, Gilbert JR, Pericak-Vance MA (May 2006). "Lack of association between autism and SLC25A12". The American Journal of Psychiatry. 163 (5): 929–31. doi:10.1176/appi.ajp.163.5.929. PMID 16648338.
• 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. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
• Hong CJ, Liou YJ, Liao DL, Hou SJ, Yen FC, Tsai SJ (October 2007). "Association study of polymorphisms in the mitochondrial aspartate/glutamate carrier SLC25A12 (aralar) gene with schizophrenia". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 31 (7): 1510–3. doi:10.1016/j.pnpbp.2007.07.010. PMID 17693006.

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