View source for Biology:Citrin

{{Short description|Mammalian protein found in humans}}
{{infobox protein
|Name=solute carrier family 25, member 13 (citrin)
|caption=The protein citrin (PDB 4P5W) is a dimer and is composed of two equal polypeptide chains.
|image=Citrin Structure.png
|width=
|HGNCid=10983
|Symbol=SLC25A13
|AltSymbols=CTLN2
|EntrezGene=10165
|OMIM=603859
|RefSeq=NM_014251
|UniProt=Q9UJS0
|PDB=
|ECnumber=
|Chromosome=7
|Arm=q
|Band=21.3
|LocusSupplementaryData=
}}
'''Citrin''', also known as '''solute carrier family 25, member 13 (citrin)''' or '''SLC25A13''', is a [[Biology:Protein|protein]] which in humans is encoded by the ''SLC25A13'' gene.<ref name="pmid10369257">{{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 | s2cid = 20137905 }}</ref>

Citrin is associated with type II [[Medicine:Citrullinemia|citrullinemia]]<ref name="pmid12111366">{{cite journal | vauthors = Saheki T, Kobayashi K | title = Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD) | journal = J. Hum. Genet. | volume = 47 | issue = 7 | pages = 333–41 | year = 2002 | pmid = 12111366 | doi = 10.1007/s100380200046 | doi-access = free }}</ref><ref name="pmid12602510">{{cite journal | vauthors = Saheki T, Kobayashi K, Iijima M, Nishi I, Yasuda T, Yamaguchi N, Gao HZ, Jalil MA, Begum L, Li MX | title = Pathogenesis and pathophysiology of citrin (a mitochondrial aspartate glutamate carrier) deficiency | journal = Metab Brain Dis | volume = 17 | issue = 4 | pages = 335–46 | year = 2002 | pmid = 12602510 | doi = 10.1023/A:1021961919148 | s2cid = 1712349 }}</ref><ref name="pmid15050970">{{cite journal | vauthors = Saheki T, Kobayashi K, Iijima M, Horiuchi M, Begum L, Jalil MA, Li MX, Lu YB, Ushikai M, Tabata A, Moriyama M, Hsiao KJ, Yang Y | title = Adult-onset type II citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency: involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle | series = 81 | journal = Mol. Genet. Metab. | volume = Suppl 1 | pages = S20–6 | year = 2004 | pmid = 15050970 | doi = 10.1016/j.ymgme.2004.01.006 }}</ref> and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD).

==Function==
Citrin (74 kDa) is a dimeric calcium-activated glutamate/aspartate carrier found in the mitochondrial membrane of mammals. Citrin is one of two isoforms of these mitochondrial calcium-activated glutamate/aspartate carriers found in humans and is predominately expressed in non-excitable tissues.<ref name="pmid25410934">{{cite journal | vauthors = Thangaratnarajah C, Ruprecht J, Kunji E | title = Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers | journal = Nat Commun | volume = 5 | issue = 5491 | year = 2014 | page = 5491 | pmid = 25410934 | doi = 10.1038/ncomms6491 | pmc = 4250520 }}</ref>

Upon binding calcium, citrin catalyzes the transport of glutamate and a proton into the mitochondrial matrix in exchange for aspartate transport to the [[Biology:Cytosol|cytosol]]. Upon being transported by citrin from the mitochondrial matrix to the cytosol, aspartate is converted into oxaloacetate, and then into malate, which is then transported back into the matrix by means of the [[Biology:Malate-aspartate shuttle|malate-aspartate shuttle]]. Upon entering the mitochondrial matrix, malate is converted back into oxaloacetate to participate in the [[Biology:Citric acid cycle|citric acid cycle]]. Citrin is also important because it supplies liver cells with aspartate that is used during the [[Chemistry:Urea cycle|urea cycle]] and [[Biology:Gluconeogenesis|gluconeogenesis]]. <ref name="pmid25410934">{{cite journal | vauthors = Thangaratnarajah C, Ruprecht J, Kunji E | title = Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers | journal = Nat Commun | volume = 5 | issue = 5491 | year = 2014 | page = 5491 | pmid = 25410934 | doi = 10.1038/ncomms6491 | pmc = 4250520 }}</ref>

==Structure==
[[File:Calcium Binding to Citrin.png|thumb|Calcium binding site within the N-terminal domain of citrin (PDB 4P5W).]]
The citrin monomer peptide has a three-domain structure, consisting of an N-terminal domain, a carrier domain, and a C-terminal domain. The N-terminal domain contains eight EF-hand motifs and is responsible for the binding of a single calcium ion. The N-terminal domain is also responsible for the dimerization of the protein to form the full glutamate/aspartate carrier. The carrier domain is responsible for transport activity and consists of six helical loops that link the N-terminal and C-terminal domains together. The C-terminal domain’s function is not fully understood yet, but it is thought to be an extra helix for the carrier domain to help account for its hydrophobicity.<ref name="pmid25410934">{{cite journal | vauthors = Thangaratnarajah C, Ruprecht J, Kunji E | title = Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers | journal = Nat Commun | volume = 5 | issue = 5491 | year = 2014 | page = 5491 | pmid = 25410934 | doi = 10.1038/ncomms6491 | pmc = 4250520 }}</ref>

Upon the binding of two calcium ions to the citrin dimer’s N-terminal domains, a structural change causes an amphipathic helix within the C-terminal domain to bind to a hydrophobic loop within the N-terminal domain, causing an opening. This opening gives the substrates such as glutamate and aspartate access to the inner carrier domain which transports them across the membrane. Upon the unbinding of calcium, the first and second EF motifs within the N-terminal domain block off and close the opening, preventing the passage of substrates.<ref name="pmid25410934">{{cite journal | vauthors = Thangaratnarajah C, Ruprecht J, Kunji E | title = Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers | journal = Nat Commun | volume = 5 | issue = 5491 | year = 2014 | page = 5491 | pmid = 25410934 | doi = 10.1038/ncomms6491 | pmc = 4250520 }}</ref>

==Diseases==
Type II citrullinemia is a liver disease caused by mutations in the ''SLC25A13'' gene, which codes for the citrin protein. Most of these mutations lead to an unfunctional citrin protein, meaning it cannot work to properly transport aspartate from the mitochondria to the cytosol. Aspartate plays a vital role in the urea cycle by reacting with [[Chemistry:Citrulline|citrulline]] to form argininosuccinate. Without adequate amounts of aspartate in the cytosol, this intermediate step in the urea cycle cannot happen, leading to an increase in the concentration of citrulline, ammonia, and other toxins since they can no longer be converted to urea by the liver. 

==See also==
* [[Biology:Solute carrier family|Solute carrier family]]

==References==
{{Reflist}}

==External links==
* {{MeshName|citrin}}
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=citrin  GeneReviews/NCBI/NIH/UW entry on Citrin Deficiency]
* {{UCSC genome browser|SLC25A13}}
* {{UCSC gene details|SLC25A13}}
* [https://citrinfoundation.org/ Citrin Foundation] non-profit funding research to cure citrin deficiency.
* [https://patient.citrinfoundation.org/en/ Citrin Foundation patient website] website with resources for citrin deficiency patients and families.

{{Membrane transport proteins}}

[[Category:Solute carrier family]]



{{Sourceattribution|Citrin}}