Biology:Calcium-binding mitochondrial carrier protein Aralar1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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 autistic people. 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. ↑ "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. September 1998. doi:10.1074/jbc.273.36.23327. PMID 9722566. 
  2. ↑ "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. Apr 2000. doi:10.1159/000015465. PMID 10702666. 
  3. ↑ "Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria". The EMBO Journal 20 (18): 5060–9. September 2001. doi:10.1093/emboj/20.18.5060. PMID 11566871. 
  4. ↑ 4.0 4.1 "Entrez Gene: SLC25A12 solute carrier family 25 (mitochondrial carrier, Aralar), member 12". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8604.  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" (in en). https://www.uniprot.org/uniprot/O75746.  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. PMID 27899622. 
  7. ↑ 7.0 7.1 "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. November 2005. doi:10.1176/appi.ajp.162.11.2182. PMID 16263864. 
  8. ↑ 8.0 8.1 "SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects". Molecular Psychiatry 13 (4): 385–97. April 2008. doi:10.1038/sj.mp.4002120. PMID 18180767. 
  9. ↑ "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. October 2013. doi:10.1161/CIRCRESAHA.113.301151. PMID 23965338. 
  10. ↑ "SLC25A12 - Calcium-binding mitochondrial carrier protein Aralar1". https://amino.heartproteome.org/web/protein/O75746. 
  11. ↑ 11.0 11.1 "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. September 1998. doi:10.1074/jbc.273.36.23327. 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. ↑ "Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers". Nature Communications 5: 5491. November 2014. doi:10.1038/ncomms6491. PMID 25410934. Bibcode: 2014NatCo...5.5491T. 
  14. ↑ "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. September 2005. doi:10.1074/jbc.M505286200. PMID 15987682. 
  15. ↑ "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. December 2004. doi:10.1074/jbc.M409303200. PMID 15494407. 
  16. ↑ IntAct. "SLC25A12 interactions" (in en). https://www.ebi.ac.uk/intact/interactors/id:O75746*#. 

Further reading

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



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