TTC19

Tetratricopeptide repeat domain 19, also known as TPR repeat protein 19 or Tetratricopeptide repeat protein 19, mitochondrial is a protein that in humans is encoded by the TTC19 gene. This gene encodes a protein with a tetratricopeptide repeat (TPR) domain containing several TPRs of about 34 amino acids each. These repeats are found in a variety of organisms including bacteria, fungi and plants, and are involved in a variety of functions including protein-protein interactions. This protein is embedded in the inner mitochondrial membrane and is involved in the formation of the mitochondrial respiratory chain III. It has also been suggested that this protein plays a role in cytokinesis. Mutations in this gene cause mitochondrial complex III deficiency. Alternatively spliced transcript variants have been found for this gene.[1]

Structure

The TTC19 gene is located on the p arm of chromosome 17 at position 12 and it spans 46,048 base pairs.[1] The TTC19 gene produces a 16 kDa protein composed of 149 amino acids.[2][3] TTC19 is a subunit of the enzyme Ubiquinol Cytochrome c Reductase (UQCR, Complex III or Cytochrome bc1 complex) of the mitochondrial respiratory chain, which consists of the products of one mitochondrially encoded gene, MTCYTB (mitochondrial cytochrome b) and ten nuclear genes: UQCRC1, UQCRC2, Cytochrome c1, UQCRFS1 (Rieske protein), UQCRB, "14kDa protein", UQCRH (cyt c1 Hinge protein), Rieske Protein presequence, "cyt. c1 associated protein", and "Rieske-associated protein".[1] The structure of the complex is a symmetric homodimer composed of one mitochondrial genome encoded cytochrome b subunit and ten other nucleus encoded subunits.[4]

Function

The TTC19 gene encodes for one of the ten nuclear proteins essential for the assembly and function of the Ubiquinol Cytochrome c Reductase or Complex III of the mitochondrial respiratory chain. The Ubiquinol Cytochrome c Reductase is responsible for catalyzing the transfer of electrons from coenzyme Q to cytochrome c as well as pumping protons from the matrix into the inner membrane which results in the generation of an ATP-coupled electrochemical potential. The TTC19 subunit is necessary for the preservation of the structural and functional integrity of Ubiquinol Cytochrome c Reductase, which is achieved by allowance of the physiological turnover of the Rieske protein (UQCRFS1).[5][6][7][8] It also participates in the clearance of UQCRFS1 N-terminal fragments which are produced by the addition of UQCRFS1 into the Ubiquinol Cytochrome c Reductase and whose presence may lead to the failure of the complex's catalytic activity.[5][6][7]

Clinical significance

Variants of TTC19 have been associated with mitochondrial complex III deficiency, nuclear 2 (MC3DN2). TTC19 is known to cause this deficiency through the failed assembly of the Ubiquinol Cytochrome c Reductase.[9] Mitochondrial complex III deficiency, nuclear (type 2) is a diverse group of neuromuscular and multi-systemic disorders caused by a dysfunction of the mitochondrial respiratory chain which may result in highly variable phenotype depending on which tissues are affected. Clinical features include mitochondrial encephalopathy, psychomotor retardation, ataxia, severe failure to thrive, liver dysfunction, renal tubulopathy, muscle weakness and exercise intolerance.[6][7][8] In addition, mutations in TTC19 is also known to be associated with various neurological disorders in both childhood and adulthood. All Pathogenic mutations of this gene have been reported to be nonsense mutations. Such mutations have included (c.937C>T; p. Q313X), (c.157_158dup), and (c.829C > T; p.Q277*).[10][11][12]

Interactions

TTC19 binds to the mature mitochondrial complex III dimer after the incorporation of the Rieske protein UQCRFS1. Additional interactions include interactions with proteins UQCRC1, UQCRFS1 (by similarity), ZFYVE26, and CHMP4B.[6][7]

References
  1. "Entrez Gene: Tetratricopeptide repeat domain 19". Retrieved 2018-08-01. This article incorporates text from this source, which is in the public domain.
  2. 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 (Oct 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.
  3. "TTC19 - Tetratricopeptide repeat protein 19, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  4. Gil Borlado MC, Moreno Lastres D, Gonzalez Hoyuela M, Moran M, Blazquez A, Pello R, Marin Buera L, Gabaldon T, Garcia Peñas JJ, Martín MA, Arenas J, Ugalde C (September 2010). "Impact of the mitochondrial genetic background in complex III deficiency". PLOS ONE. 5 (9): e12801. Bibcode:2010PLoSO...512801G. doi:10.1371/journal.pone.0012801. PMC 2941448. PMID 20862300.
  5. Bottani, E; Cerutti, R; Harbour, ME; Ravaglia, S; Dogan, SA; Giordano, C; Fearnley, IM; D'Amati, G; Viscomi, C; Fernandez-Vizarra, E; Zeviani, M (6 July 2017). "TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III". Molecular Cell. 67 (1): 96–105.e4. doi:10.1016/j.molcel.2017.06.001. PMID 28673544.
  6. "TTC19 - Tetratricopeptide repeat protein 19, mitochondrial precursor - Homo sapiens (Human) - TTC19 gene & protein". www.uniprot.org. Retrieved 2018-07-31. This article incorporates [www.uniprot.org text] by UniProt available under the CC BY 4.0 license.
  7. "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
  8. Ghezzi D, Arzuffi P, Zordan M, Da Re C, Lamperti C, Benna C, D'Adamo P, Diodato D, Costa R, Mariotti C, Uziel G, Smiderle C, Zeviani M (March 2011). "Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies". Nat. Genet. 43 (3): 259–63. doi:10.1038/ng.761. PMID 21278747. S2CID 22966332.
  9. Nogueira C, Barros J, Sá MJ, Azevedo L, Taipa R, Torraco A, Meschini MC, Verrigni D, Nesti C, Rizza T, Teixeira J, Carrozzo R, Pires MM, Vilarinho L, Santorelli FM (May 2013). "Novel TTC19 mutation in a family with severe psychiatric manifestations and complex III deficiency". Neurogenetics. 14 (2): 153–60. doi:10.1007/s10048-013-0361-1. PMID 23532514. S2CID 6618051.
  10. Morino H, Miyamoto R, Ohnishi S, Maruyama H, Kawakami H (January 2014). "Exome sequencing reveals a novel TTC19 mutation in an autosomal recessive spinocerebellar ataxia patient". BMC Neurol. 14: 5. doi:10.1186/1471-2377-14-5. PMC 3890717. PMID 24397319.
  11. Mordaunt DA, Jolley A, Balasubramaniam S, Thorburn DR, Mountford HS, Compton AG, Nicholl J, Manton N, Clark D, Bratkovic D, Friend K, Yu S (June 2015). "Phenotypic variation of TTC19-deficient mitochondrial complex III deficiency: a case report and literature review". Am. J. Med. Genet. A. 167 (6): 1330–6. doi:10.1002/ajmg.a.36968. PMID 25899669. S2CID 27159035.
  12. Kunii, M; Doi, H; Higashiyama, Y; Kugimoto, C; Ueda, N; Hirata, J; Tomita-Katsumoto, A; Kashikura-Kojima, M; Kubota, S; Taniguchi, M; Murayama, K; Nakashima, M; Tsurusaki, Y; Miyake, N; Saitsu, H; Matsumoto, N; Tanaka, F (April 2015). "A Japanese case of cerebellar ataxia, spastic paraparesis and deep sensory impairment associated with a novel homozygous TTC19 mutation". Journal of Human Genetics. 60 (4): 187–91. doi:10.1038/jhg.2015.7. PMID 25652355. S2CID 25347926.

Further reading

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

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