Calcium-binding mitochondrial carrier protein Aralar1

Structure

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

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. 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. 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. 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.

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.

Autism

2 SNPs in introns 3 and 16 of the SLC25A12 gene may be associated with autism. 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.

Interactions

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

References

References

1. (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.
2. (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.
3. (September 2001). "Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria". The EMBO Journal.
4. "Entrez Gene: SLC25A12 solute carrier family 25 (mitochondrial carrier, Aralar), member 12".
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6. (January 2017). "UniProt: the universal protein knowledgebase". Nucleic Acids Research.
7. (November 2005). "Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31". The American Journal of Psychiatry.
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10. (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.
11. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: {603667}: {08/01/2016}: . World Wide Web URL: https://omim.org/
12. (November 2014). "Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers". Nature Communications.
13. (September 2005). "Reduced N-acetylaspartate levels in mice lacking aralar, a brain- and muscle-type mitochondrial aspartate-glutamate carrier". The Journal of Biological Chemistry.
14. (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.
15. (April 2008). "SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects". Molecular Psychiatry.
16. IntAct. "SLC25A12 interactions".