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{{Infobox_gene}}
{{PBB_Controls
'''Calcium-binding mitochondrial carrier protein Aralar1''' is a [[protein]] that in humans is encoded by the ''SLC25A12'' [[gene]].<ref name="pmid9722566">{{cite journal | vauthors = del Arco A, Satrústegui J | title = Molecular cloning of Aralar, a new member of the mitochondrial carrier superfamily that binds calcium and is present in human muscle and brain | journal = The Journal of Biological Chemistry | volume = 273 | issue = 36 | pages = 23327–34 | date = September 1998 | pmid = 9722566 | pmc =  | doi = 10.1074/jbc.273.36.23327 }}</ref><ref name="pmid10702666">{{cite journal | vauthors = Crackower MA, Sinasac DS, Lee JR, Herbrick JA, Tsui LC, Scherer SW | title = Assignment of the SLC25A12 gene coding for the human calcium-binding mitochondrial solute carrier protein aralar to human chromosome 2q24 | journal = Cytogenetics and Cell Genetics | volume = 87 | issue = 3–4 | pages = 197–8 | date = Apr 2000 | pmid = 10702666 | pmc =  | doi = 10.1159/000015465 }}</ref><ref name="pmid11566871">{{cite journal | vauthors = Palmieri L, Pardo B, Lasorsa FM, del Arco A, Kobayashi K, Iijima M, Runswick MJ, Walker JE, Saheki T, Satrústegui J, Palmieri F | title = Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria | journal = The EMBO Journal | volume = 20 | issue = 18 | pages = 5060–9 | date = September 2001 | pmid = 11566871 | pmc = 125626 | doi = 10.1093/emboj/20.18.5060 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SLC25A12 solute carrier family 25 (mitochondrial carrier, Aralar), member 12| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8604| access-date = }}{{PD-notice}}</ref> Aralar is an [[integral membrane protein]] located in the [[inner mitochondrial membrane]]. Its primary function as an [[antiporter]] is the [[Membrane transport|transport]] of [[cytoplasm|cytoplasmic]] [[glutamic acid|glutamate]] with [[mitochondrion|mitochondrial]] [[aspartic acid|aspartate]] across the inner mitochondrial membrane, dependent on the binding of one [[Calcium in biology|calcium]] [[ion]]. [[Mutation]]s in this gene cause early infantile [[epilepsy|epileptic]] [[encephalopathy]] 39 (EIEE39), symptomized by global hypomyelination of the [[central nervous system]], refractory [[Epileptic_seizure|seizures]], and [[Neurodevelopmental disorder|neurodevelopmental impairment]].<ref name=":0">{{Cite web|url=https://www.uniprot.org/uniprot/O75746|title=SLC25A12 - Calcium-binding mitochondrial carrier protein Aralar1 - Homo sapiens (Human) - SLC25A12 gene & protein|website=www.uniprot.org|language=en|access-date=2018-08-22}}{{CC-notice|cc=by4}}</ref><ref name=":3">{{cite journal | vauthors =  | title = UniProt: the universal protein knowledgebase | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D158-D169 | date = January 2017 | pmid = 27899622 | pmc = 5210571 | doi = 10.1093/nar/gkw1099 }}</ref> This gene has connections to [[autism]].<ref name=":2">{{cite journal | vauthors = Segurado R, Conroy J, Meally E, Fitzgerald M, Gill M, Gallagher L | title = Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31 | journal = The American Journal of Psychiatry | volume = 162 | issue = 11 | pages = 2182–4 | date = November 2005 | pmid = 16263864 | doi = 10.1176/appi.ajp.162.11.2182 | hdl = 2262/34993 }}</ref><ref name=":4" />
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
== Structure ==
{{GNF_Protein_box
The ''SLC25A12'' gene is located on the q arm of [[chromosome 2]] in position 31.1 and spans 110,902 base pairs.<ref name = "entrez"/> The gene produces a 74.8 kDa protein composed of 678 [[amino acids]].<ref name=COPaKB>{{cite journal | vauthors = 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 | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}</ref><ref name="url_COPaKB">{{cite web | url = https://amino.heartproteome.org/web/protein/O75746 | website = Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) | title = SLC25A12 - Calcium-binding mitochondrial carrier protein Aralar1 }}</ref> The encoded protein, Aralar1, is a [[Integral_membrane_protein#Integral_polytopic_protein|multi-pass membrane protein]] located in the inner mitochondrial membrane.<ref name=":0" /><ref name=":3" /> The [[N-terminus|N-terminal]] half of this protein contains 2 imperfect [[EF hand|EF-hand]] [[protein domain|domains]] along with 3 canonical EF-hand calcium-binding domains; this part of the protein binds calcium in vitro. Aralar's [[C-terminus|C-terminal]] half shares 28-29% [[Sequence_homology#Identity,_similarity,_and_conservation|identity]] with other members of the [[Mitochondrial_carrier|mitochondrial solute carrier]] [[protein family|family]], including [[SLC25A11]], [[SLC25A5]], [[SLC25A1]], and has 6 [[Putative gene|putative]] [[Transmembrane_domain|transmembrane domains]] like the other members of mitochondrial [[solute carrier family]].<ref name=":5">{{cite journal | vauthors = del Arco A, Satrústegui J | title = Molecular cloning of Aralar, a new member of the mitochondrial carrier superfamily that binds calcium and is present in human muscle and brain | journal = The Journal of Biological Chemistry | volume = 273 | issue = 36 | pages = 23327–34 | date = September 1998 | pmid = 9722566 }}</ref><ref name=":1">Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: {603667}: {08/01/2016}: . World Wide Web URL: https://omim.org/</ref>  
| image =
| image_source = 
| PDB =
| Name = Solute carrier family 25 (mitochondrial carrier, Aralar), member 12
| HGNCid = 10982
| Symbol = SLC25A12
| AltSymbols =; ARALAR; ARALAR1
| OMIM = 603667
| ECnumber =
| Homologene = 48235
| MGIid = 1926080
| GeneAtlas_image1 = PBB_GE_SLC25A12_203340_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_SLC25A12_203339_at_tn.png
| Function = {{GNF_GO|id=GO:0005215 |text = transporter activity}} {{GNF_GO|id=GO:0005488 |text = binding}} {{GNF_GO|id=GO:0005509 |text = calcium ion binding}} {{GNF_GO|id=GO:0015294 |text = solute:cation symporter activity}}
| Component = {{GNF_GO|id=GO:0005739 |text = mitochondrion}} {{GNF_GO|id=GO:0005743 |text = mitochondrial inner membrane}} {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0016020 |text = membrane}}
| Process = {{GNF_GO|id=GO:0006810 |text = transport}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 8604
    | Hs_Ensembl = ENSG00000115840
    | Hs_RefseqProtein = NP_003696
    | Hs_RefseqmRNA = NM_003705
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 2
    | Hs_GenLoc_start = 172349127
    | Hs_GenLoc_end = 172458991
    | Hs_Uniprot = O75746
    | Mm_EntrezGene = 78830
    | Mm_Ensembl = ENSMUSG00000027010
    | Mm_RefseqmRNA = NM_172436
    | Mm_RefseqProtein = NP_766024
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 2
    | Mm_GenLoc_start = 71071902
    | Mm_GenLoc_end = 71168588
    | Mm_Uniprot = Q8BH59
  }}
}}
'''Solute carrier family 25 (mitochondrial carrier, Aralar), member 12''', also known as '''SLC25A12''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: SLC25A12 solute carrier family 25 (mitochondrial carrier, Aralar), member 12| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8604| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
== Function ==
{{PBB_Summary
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 [[Ligand_(biochemistry)#Receptor/ligand_binding_affinity|affinity]]. Upon calcium binding, the EF-hand-containing regulatory N-terminal domain binds to the C-terminal domain, opening a vestibule which allows the [[Substrate (biochemistry)|substrate]]s 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.<ref>{{cite journal | vauthors = Thangaratnarajah C, Ruprecht JJ, Kunji ER | title = Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers | journal = Nature Communications | volume = 5 | pages = 5491 | date = November 2014 | pmid = 25410934 | pmc = 4250520 | doi = 10.1038/ncomms6491 }}</ref> As a member of the [[malic acid|malate]]-aspartate [[Nicotinamide adenine dinucleotide|NADH]] [[Malate-aspartate shuttle|shuttle]], Aralar is also involved in the transfer of cytosolic [[Reducing equivalent|reducing equivalents]] from the cytosol to the [[mitochondrial matrix]].<ref>{{cite journal | vauthors = 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 | title = Reduced N-acetylaspartate levels in mice lacking aralar, a brain- and muscle-type mitochondrial aspartate-glutamate carrier | journal = The Journal of Biological Chemistry | volume = 280 | issue = 35 | pages = 31333–9 | date = September 2005 | pmid = 15987682 | doi = 10.1074/jbc.M505286200 }}</ref> Aralar, along with the protein encoded by ''SLC25A13'', are both calcium-binding aspartate/glutamate carriers which are substrates in the [[TIMM8A]]/[[TIMM13]] [[protein complex|complex]].
| section_title =  
| summary_text =  
}}


==See also==
== Clinical Significance ==
[[Gene expression|Overexpression]] of Aralar1 augments mitochondrial [[Metabolism#Oxidative_phosphorylation|metabolism]] and increases [[insulin]] secretion in [[Beta cell|pancreatic cells]].<ref>{{cite journal | vauthors = Rubi B, del Arco A, Bartley C, Satrustegui J, Maechler P | title = The malate-aspartate NADH shuttle member Aralar1 determines glucose metabolic fate, mitochondrial activity, and insulin secretion in beta cells | journal = The Journal of Biological Chemistry | volume = 279 | issue = 53 | pages = 55659–66 | date = December 2004 | pmid = 15494407 | doi = 10.1074/jbc.M409303200 | url = http://www.jbc.org/content/279/53/55659 }}</ref> Aralar is expressed as both a 3.2 kb and 2.9 kb mRNA [[Primary transcript|transcript]] in [[Cardiac muscle cell|heart]] and [[skeletal muscle]] cells, and in lesser amounts in [[neuron|brain]] and [[kidney]] cells.<ref name=":5" /><ref name=":1" />
 
=== 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 [[Age of onset|onset]], after which cognitive and motor delays become apparent. EIEE39 is characterized by global hypomyelination of the central nervous system, with the [[Grey matter|gray matter]] appearing relatively unaffected. Inheritance is [[Genetic_disorder#Autosomal_recessive|autosomal recessive]].<ref name=":0" /><ref name=":3" />
 
=== Autism ===
2 [[Single-nucleotide polymorphism|SNPs]] in [[intron]]s 3 and 16 of the ''SLC25A12'' gene may be associated with [[autism]].<ref name=":2" /> In [[Brodmann area 46|Brodmann's Area (BA) 46]] of the [[prefrontal cortex]], ''SLC25A12'' is expressed more strongly in the neurons of those suffering from autism. SLC25A12 overexpression may modify [[Neural network|neuronal networks]] in certain subregions of the brain during the [[Prenatal development|fetal development]] of autistic patients.<ref name=":4">{{cite journal | vauthors = 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 | title = SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects | journal = Molecular Psychiatry | volume = 13 | issue = 4 | pages = 385–97 | date = April 2008 | pmid = 18180767 | doi = 10.1038/sj.mp.4002120 }}</ref>
 
== Interactions ==
Aralar has [[protein-protein interactions|interactions]] with [[SCO1]], [[ATF2]], [[COX14]], [[COA3]], in addition to 36 other proteins.<ref>{{Cite web|url=https://www.ebi.ac.uk/intact/interactors/id:O75746*#|title=SLC25A12 interactions|last=IntAct|website=www.ebi.ac.uk|language=en|access-date=2018-08-23}}</ref>
 
== See also ==
* [[Solute carrier family]]
* [[Solute carrier family]]


==References==
== References ==
{{reflist|2}}
{{reflist}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = 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 | title = The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein | journal = Nature Genetics | volume = 22 | issue = 2 | pages = 159–63 | date = June 1999 | pmid = 10369257 | doi = 10.1038/9667 }}
| citations =
* {{cite journal | vauthors = Sanz R, del Arco A, Ayuso C, Ramos C, Satrústegui J | title = Assignment of the calcium-binding mitochondrial carrier Aralar1 gene (SLC25A12) to human chromosome band 2q31 by in situ hybridization | journal = Cytogenetics and Cell Genetics | volume = 89 | issue = 3–4 | pages = 143–4 | year = 2000 | pmid = 10965105 | doi = 10.1159/000015595 }}
*{{cite journal | author=del Arco A, Satrústegui J |title=Molecular cloning of Aralar, a new member of the mitochondrial carrier superfamily that binds calcium and is present in human muscle and brain. |journal=J. Biol. Chem. |volume=273 |issue= 36 |pages= 23327-34 |year= 1998 |pmid= 9722566 |doi=  }}
* {{cite journal | vauthors = Ramoz N, Reichert JG, Smith CJ, Silverman JM, Bespalova IN, Davis KL, Buxbaum JD | title = Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism | journal = The American Journal of Psychiatry | volume = 161 | issue = 4 | pages = 662–9 | date = April 2004 | pmid = 15056512 | doi = 10.1176/appi.ajp.161.4.662 }}
*{{cite journal  | author=Kobayashi K, Sinasac DS, Iijima M, ''et al.'' |title=The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. |journal=Nat. Genet. |volume=22 |issue= 2 |pages= 159-63 |year= 1999 |pmid= 10369257 |doi= 10.1038/9667 }}
* {{cite journal | vauthors = Rubi B, del Arco A, Bartley C, Satrustegui J, Maechler P | title = The malate-aspartate NADH shuttle member Aralar1 determines glucose metabolic fate, mitochondrial activity, and insulin secretion in beta cells | journal = The Journal of Biological Chemistry | volume = 279 | issue = 53 | pages = 55659–66 | date = December 2004 | pmid = 15494407 | doi = 10.1074/jbc.M409303200 }}
*{{cite journal | author=Crackower MA, Sinasac DS, Lee JR, ''et al.'' |title=Assignment of the SLC25A12 gene coding for the human calcium-binding mitochondrial solute carrier protein aralar to human chromosome 2q24. |journal=Cytogenet. Cell Genet. |volume=87 |issue= 3-4 |pages= 197-8 |year= 2000 |pmid= 10702666 |doi=  }}
* {{cite journal | vauthors = 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 | title = Lack of association between autism and SLC25A12 | journal = The American Journal of Psychiatry | volume = 163 | issue = 5 | pages = 929–31 | date = May 2006 | pmid = 16648338 | doi = 10.1176/appi.ajp.163.5.929 }}
*{{cite journal  | author=Sanz R, del Arco A, Ayuso C, ''et al.'' |title=Assignment of the calcium-binding mitochondrial carrier Aralar1 gene (SLC25A12) to human chromosome band 2q31 by in situ hybridization. |journal=Cytogenet. Cell Genet. |volume=89 |issue= 3-4 |pages= 143-4 |year= 2000 |pmid= 10965105 |doi=  }}
* {{cite journal | vauthors = 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 | title = Large-scale mapping of human protein-protein interactions by mass spectrometry | journal = Molecular Systems Biology | volume = 3 | issue = 1 | pages = 89 | year = 2007 | pmid = 17353931 | pmc = 1847948 | doi = 10.1038/msb4100134 }}
*{{cite journal  | author=Palmieri L, Pardo B, Lasorsa FM, ''et al.'' |title=Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. |journal=EMBO J. |volume=20 |issue= 18 |pages= 5060-9 |year= 2001 |pmid= 11566871 |doi= 10.1093/emboj/20.18.5060 }}
* {{cite journal | vauthors = Hong CJ, Liou YJ, Liao DL, Hou SJ, Yen FC, Tsai SJ | title = Association study of polymorphisms in the mitochondrial aspartate/glutamate carrier SLC25A12 (aralar) gene with schizophrenia | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 31 | issue = 7 | pages = 1510–3 | date = October 2007 | pmid = 17693006 | doi = 10.1016/j.pnpbp.2007.07.010 }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
*{{cite journal  | author=Ramoz N, Reichert JG, Smith CJ, ''et al.'' |title=Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. |journal=The American journal of psychiatry |volume=161 |issue= 4 |pages= 662-9 |year= 2004 |pmid= 15056512 |doi= }}
*{{cite journal | author=Rubi B, del Arco A, Bartley C, ''et al.'' |title=The malate-aspartate NADH shuttle member Aralar1 determines glucose metabolic fate, mitochondrial activity, and insulin secretion in beta cells. |journal=J. Biol. Chem. |volume=279 |issue= 53 |pages= 55659-66 |year= 2005 |pmid= 15494407 |doi= 10.1074/jbc.M409303200 }}
*{{cite journal | author=Rabionet R, McCauley JL, Jaworski JM, ''et al.'' |title=Lack of association between autism and SLC25A12. |journal=The American journal of psychiatry |volume=163 |issue= 5 |pages= 929-31 |year= 2006 |pmid= 16648338 |doi= 10.1176/appi.ajp.163.5.929 }}
*{{cite journal | author=Ewing RM, Chu P, Elisma F, ''et al.'' |title=Large-scale mapping of human protein-protein interactions by mass spectrometry. |journal=Mol. Syst. Biol. |volume=3 |issue= |pages= 89 |year= 2007 |pmid= 17353931 |doi= 10.1038/msb4100134 }}
*{{cite journal | author=Hong CJ, Liou YJ, Liao DL, ''et al.'' |title=Association study of polymorphisms in the mitochondrial aspartate/glutamate carrier SLC25A12 (aralar) gene with schizophrenia. |journal=Prog. Neuropsychopharmacol. Biol. Psychiatry |volume=31 |issue= 7 |pages= 1510-3 |year= 2007 |pmid= 17693006 |doi= 10.1016/j.pnpbp.2007.07.010 }}
}}
{{refend}}
{{refend}}


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[[Category:EF-hand-containing proteins]]

Latest revision as of 10:21, 16 September 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

Calcium-binding mitochondrial carrier protein Aralar1 is a protein that in humans is encoded by the SLC25A12 gene.[1][2][3][4] 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.[5][6] This gene has connections to autism.[7][8]

Structure

The SLC25A12 gene is located on the q arm of chromosome 2 in position 31.1 and spans 110,902 base pairs.[4] The gene produces a 74.8 kDa protein composed of 678 amino acids.[9][10] The encoded protein, Aralar1, is a multi-pass membrane protein located in the inner mitochondrial membrane.[5][6] 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.[11][12]

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.[13] 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.[14] 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.[15] 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.[11][12]

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.[5][6]

Autism

2 SNPs in introns 3 and 16 of the SLC25A12 gene may be associated with autism.[7] In Brodmann's Area (BA) 46 of the prefrontal cortex, SLC25A12 is expressed more strongly in the neurons of those suffering from autism. SLC25A12 overexpression may modify neuronal networks in certain subregions of the brain during the fetal development of autistic patients.[8]

Interactions

Aralar has interactions with SCO1, ATF2, COX14, COA3, in addition to 36 other proteins.[16]

See also

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 4.0 4.1 "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.
  5. ↑ 5.0 5.1 5.2 "SLC25A12 - Calcium-binding mitochondrial carrier protein Aralar1 - Homo sapiens (Human) - SLC25A12 gene & protein". www.uniprot.org. Retrieved 2018-08-22.File:CC-BY-icon-80x15.png This article incorporates text available under the CC BY 4.0 license.
  6. ↑ 6.0 6.1 6.2 "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
  7. ↑ 7.0 7.1 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.
  8. ↑ 8.0 8.1 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.
  9. ↑ 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.
  10. ↑ "SLC25A12 - Calcium-binding mitochondrial carrier protein Aralar1". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  11. ↑ 11.0 11.1 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. PMID 9722566.
  12. ↑ 12.0 12.1 Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: {603667}: {08/01/2016}: . World Wide Web URL: https://omim.org/
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.

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