TIMM50

{{Short description|Protein-coding gene in the species Homo sapiens}} {{Infobox_gene}} '''Mitochondrial import inner membrane translocase subunit TIM50''' is a protein that in humans is encoded by the ''TIMM50'' gene. Tim50 is a subunit of the Tim23 translocase complex in the inner mitochondrial membrane.<ref name="pmid12437925">{{cite journal | vauthors = Yamamoto H, Esaki M, Kanamori T, Tamura Y, Nishikawa S, Endo T | title = TIM50 is a subunit of the Tim23 complex which links protein translocation across the outer and inner mitochondrial membranes | journal = Cell | volume = 111 | issue = 4 | pages = 519–28 | date = November 2002 | pmid = 12437925 | doi = 10.1016/S0092-8674(02)01053-X | s2cid = 18869447 | doi-access = free }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: TIMM50 translocase of inner mitochondrial membrane 50 homolog (S. cerevisiae)| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=92609 }}</ref> Mutations in ''TIMM50'' can lead to epilepsy, severe intellectual disability, and 3-methylglutaconic aciduria.<ref name="Shahrour_2017">{{cite journal | vauthors = Shahrour MA, Staretz-Chacham O, Dayan D, Stephen J, Weech A, Damseh N, Pri Chen H, Edvardson S, Mazaheri S, Saada A, Hershkovitz E, Shaag A, Huizing M, Abu-Libdeh B, Gahl WA, Azem A, Anikster Y, Vilboux T, Elpeleg O, Malicdan MC | display-authors = 6 | title = Mitochondrial epileptic encephalopathy, 3-methylglutaconic aciduria and variable complex V deficiency associated with TIMM50 mutations | journal = Clinical Genetics | volume = 91 | issue = 5 | pages = 690–696 | date = May 2017 | pmid = 27573165 | doi = 10.1111/cge.12855 | s2cid = 22348518 | pmc = 8359539 }}</ref> ''TIMM50'' expression is increased in breast cancer cells<ref name="Gao_2016">{{cite journal | vauthors = Gao SP, Sun HF, Jiang HL, Li LD, Hu X, Xu XE, Jin W | title = Loss of TIM50 suppresses proliferation and induces apoptosis in breast cancer | journal = Tumor Biology | volume = 37 | issue = 1 | pages = 1279–87 | date = January 2016 | pmid = 26289846 | doi = 10.1007/s13277-015-3878-0 | s2cid = 36502903 }}</ref> and decreased in hypertrophic hearts.<ref name="Tang_2017">{{cite journal | vauthors = Tang K, Zhao Y, Li H, Zhu M, Li W, Liu W, Zhu G, Xu D, Peng W, Xu YW | display-authors = 6 | title = Translocase of Inner Membrane 50 Functions as a Novel Protective Regulator of Pathological Cardiac Hypertrophy | journal = Journal of the American Heart Association | volume = 6 | issue = 4 | article-number = e004346 | date = April 2017 | pmid = 28432072 | doi = 10.1161/JAHA.116.004346 | pmc = 5532988 }}</ref>

== Structure == The ''TIMM50'' gene is located on the q arm of chromosome 19 in position 13.2 and spans 13,373 base pairs.<ref name = "entrez"/> The gene produces a 39.6 kDa protein composed of 353 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 | display-authors = 6 | 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/Q3ZCQ8 | work = Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) | title = Mitochondrial import inner membrane translocase subunit TIM50 | access-date = 2018-07-20 | archive-date = 2018-07-21 | archive-url = https://web.archive.org/web/20180721014225/https://amino.heartproteome.org/web/protein/Q3ZCQ8 }}</ref> This gene encodes a subunit of the TIM23 inner mitochondrial membrane translocase complex, which mediates the translocation of transit peptide-containing proteins across the mitochondrial inner membrane.<ref name = "entrez"/>

== Function == The Tim50 protein functions as the receptor subunit that recognizes the mitochondrial targeting signal, or presequence, on protein cargo that is destined for the mitochondrial inner membrane and matrix. Knockdown of this gene in human cells results in the release of cytochrome c and apoptosis.<ref name = "entrez"/> This protein plays a role in maintaining the membrane permeability barrier. The intermembrane space domain of Tim50 induces the translocation pore of the TIM23 channel to close.<ref name="pmid12437925"/><ref name="entrez"/>

== Clinical significance == Missense mutations in ''TIMM50'' often result in epilepsy or epileptic encephalopathy, severe intellectual disability, variable mitochondrial complex V deficiency, and 3-methylglutaconic aciduria, which is a key biomarker for mitochondrial membrane defects and mitochondrial dysfunction. Inheritance of ''TIMM50'' is autosomal recessive.<ref name="Shahrour_2017" /> Expression of the TIMM50 gene is increased in breast cancer cells. In such cells, overexpression of the Tim50 protein is linked to lack of cellular apoptosis and increased rates of proliferation.<ref name="Gao_2016" /> Decreased ''TIMM50'' expression in heart cells can lead to cardiac hypertrophy.<ref name="Tang_2017" />

Two patients, male and female siblings born to consanguineous Bedouin parents were presented, displaying involuntary abnormal movements, failure to thrive, hypsarrhythmia, bilateral optic atrophy, 3-methylglutaconic aciduria, and slightly elevated plasma lactate levels. Both began walking independently at only 3 years and initially received favorably ACTH therapy until switching to a treatment of Valproate with either Sabril or Topamax, which resulted in seizures completely disappearing. Two more patients, male and female siblings born to first-cousin parents of Muslim origin were also presented, displaying myoclonic and tonic seizures, abnormal EEG, brain atrophy, delayed psychomotor development and 3-methylglutaconic aciduria. Treatment of Lamictal combined with Valproate was effective in controlling the seizures.<ref name="Shahrour_2017" />

== Interactions == Within the TIM23 complex, the Tim50 subunit directly interacts with ''TIMM23''. The TIM23 complex interacts with the ''TIMM44'' component of the PAM complex and with ''DNAJC15''. An isoform of Tim50 interacts with ''COIL'' and snRNPs.<ref>{{Cite web|url=https://www.uniprot.org/uniprot/Q3ZCQ8|title=TIMM50 - Mitochondrial import inner membrane translocase subunit TIM50 precursor - Homo sapiens (Human) - TIMM50 gene & protein|website=www.uniprot.org|language=en|access-date=2018-07-25}}</ref>

== References == {{reflist}}

== Further reading == {{refbegin | 2}} * {{cite journal | vauthors = Xu H, Somers ZB, Robinson ML, Hebert MD | title = Tim50a, a nuclear isoform of the mitochondrial Tim50, interacts with proteins involved in snRNP biogenesis | journal = BMC Cell Biology | volume = 6 | issue = 1 | article-number = 29 | date = July 2005 | pmid = 16008839 | pmc = 1177934 | doi = 10.1186/1471-2121-6-29 | doi-access = free }} * {{cite journal | vauthors = Guo Y, Cheong N, Zhang Z, De Rose R, Deng Y, Farber SA, Fernandes-Alnemri T, Alnemri ES | title = Tim50, a component of the mitochondrial translocator, regulates mitochondrial integrity and cell death | journal = The Journal of Biological Chemistry | volume = 279 | issue = 23 | pages = 24813–25 | date = June 2004 | pmid = 15044455 | doi = 10.1074/jbc.M402049200 | doi-access = free }} * {{cite journal | vauthors = Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G | display-authors = 6 | title = A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway | journal = Nature Cell Biology | volume = 6 | issue = 2 | pages = 97–105 | date = February 2004 | pmid = 14743216 | doi = 10.1038/ncb1086 | s2cid = 11683986 }} * {{cite journal | vauthors = Yuryev A, Wennogle LP | title = Novel raf kinase protein-protein interactions found by an exhaustive yeast two-hybrid analysis | journal = Genomics | volume = 81 | issue = 2 | pages = 112–25 | date = February 2003 | pmid = 12620389 | doi = 10.1016/S0888-7543(02)00008-3 }} {{refend}}