FOXRED1
| FOXRED1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | FOXRED1, H17, FP634, FAD-dependent oxidoreductase domain containing 1, FAD dependent oxidoreductase domain containing 1, MC1DN19 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 613622; MGI: 2446262; HomoloGene: 9712; GeneCards: FOXRED1; OMA:FOXRED1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1), also known as H17, or FP634 is an enzyme that in humans is encoded by the FOXRED1 gene.[5][6] FOXRED1 is an oxidoreductase and complex I-specific molecular chaperone involved in the assembly and stabilization of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[7][8][9] Mutations in FOXRED1 have been associated with Leigh syndrome[10][11] and infantile-onset mitochondrial encephalopathy.[8]
Structure
[edit]FOXRED1 is located on the q arm of chromosome 11 in position 14.2 and has 12 exons.[5] The FOXRED1 gene produces a 53.8 kDa protein composed of 486 amino acids.[12][13] Alternatively spliced transcript variants have been observed for this gene.[5]
FOXRED1 contains an oxidoreductase FAD-binding domain and is homologous to FAD-binding proteins dimethylglycine dehydrogenase, sarcosine dehydrogenase, L-pipecolic acid oxidase, peroxisomal sarcosine oxidase, and pyrvuvate dehydrogenase regulatory subunit. FOXRED1's structural similarities to sarcosine oxidase (MSOX) predict that tyrosine residues Y410 and Y411 make up the site of covalent attachment of FAD. Additionally, a phenyl moiety at p. 359 is thought to be critical for function.[8][10] Finally, FOXRED1 is a matrix-directed protein that is thought to be imported through the presence of a mitochondrial membrane potential rather than through a cleavable targeting signal.[10] However, others suggest that it contains a 23 amino acid N-terminal mitochondrial localization sequence and that this sequence is cleaved upon entry to form the mature protein.[8]
Function
[edit]The FOXRED1 gene encodes an enzyme that is localized in the mitochondria and which helps in the assembly and stabilization of NADH:ubiquinone oxidoreductase, a large multi-subunit enzyme in the mitochondrial respiratory chain.[5][10] NADH:ubiquinone oxidoreductase (complex I) is involved in several physiological activities in the cell, including metabolite transport and ATP synthesis. Complex I catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane.[14] The encoded protein of FOXRED1 is an oxidoreductase and complex I-specific molecular chaperone. It plays a role in the mid-to-late stages of complex I intermediate assembly and is important for the assembly, stabilization, and function of complex I. It is proposed that FOXRED1 functions in a complex with core subunit NDUFS3 as well as accessory subunits NDUFA5, NDUFA10, NDUFB10 and NDUFS5.[10]
Clinical Significance
[edit]Mutations in FOXRED1 can result in mitochondrial deficiencies and associated disorders. A disorder of the mitochondrial respiratory chain can cause a wide range of clinical manifestations from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.[9] Pathogenic mutations of FOXRED1 have included c.1054C>T; p.R352W, c.694C>T; p.Q232X, and c.1289A>G; p.N430S. Symptoms due to these mutations have included lactic acidosis, hypertrophic cardiomyopathy, and optic atrophy. Clinically, these variants have been associated with Leigh syndrome[10][11] and infantile-onset mitochondrial encephalopathy.[8] Survival with FOXRED1 mutations appears to be more common than in other complex I deficiencies and overexpression of mutant forms can lead to rescued complex I activity indicating that FOXRED1 activity can be compensated for to some degree.[10]
Interactions
[edit]FOXRED1 co-immunoprecipitates with complex I subunits NDUFB10, NDUFS5, NDUFA10, NDUFA8, NDUFS3 and NDUFA5 and may be associated with import machinery Tom20, Tom22 and MPP as well as chaperones mtHsp70, Hsp60, and Hsp10.[10] In addition to co-complexes and potential associations, FOXRED1 has been confirmed to have protein-protein interactions with EXOSC10.[15]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000110074 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000039048 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c d "Entrez Gene: FOXRED1 FAD-dependent oxidoreductase domain containing 1".
- ^ Oh JJ, Grosshans DR, Wong SG, Slamon DJ (October 1999). "Identification of differentially expressed genes associated with HER-2/neu overexpression in human breast cancer cells". Nucleic Acids Research. 27 (20): 4008–17. doi:10.1093/nar/27.20.4008. PMC 148668. PMID 10497265.
- ^ Voet D, Voet JG, Pratt CW (2013). "18". Fundamentals of biochemistry: life at the molecular level (4th ed.). Hoboken, NJ: Wiley. pp. 581–620. ISBN 9780470547847.
- ^ a b c d e Fassone E, Duncan AJ, Taanman JW, Pagnamenta AT, Sadowski MI, Holand T, Qasim W, Rutland P, Calvo SE, Mootha VK, Bitner-Glindzicz M, Rahman S (December 2010). "FOXRED1, encoding an FAD-dependent oxidoreductase complex-I-specific molecular chaperone, is mutated in infantile-onset mitochondrial encephalopathy". Human Molecular Genetics. 19 (24): 4837–47. doi:10.1093/hmg/ddq414. PMC 4560042. PMID 20858599.
- ^ a b "FOXRED1 - FAD-dependent oxidoreductase domain-containing protein 1 - Homo sapiens (Human) - FOXRED1 gene & protein". uniprot.org. Retrieved 2018-07-27.
- ^ a b c d e f g h Formosa LE, Mimaki M, Frazier AE, McKenzie M, Stait TL, Thorburn DR, Stroud DA, Ryan MT (May 2015). "Characterization of mitochondrial FOXRED1 in the assembly of respiratory chain complex I". Human Molecular Genetics. 24 (10): 2952–65. doi:10.1093/hmg/ddv058. hdl:10536/DRO/DU:30112237. PMID 25678554.
- ^ a b Calvo SE, Tucker EJ, Compton AG, Kirby DM, Crawford G, Burtt NP, Rivas M, Guiducci C, Bruno DL, Goldberger OA, Redman MC, Wiltshire E, Wilson CJ, Altshuler D, Gabriel SB, Daly MJ, Thorburn DR, Mootha VK (October 2010). "High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency". Nature Genetics. 42 (10): 851–8. doi:10.1038/ng.659. PMC 2977978. PMID 20818383.
- ^ 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 (October 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.
- ^ Yao, Daniel. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information". amino.heartproteome.org. Retrieved 2018-07-27.[permanent dead link]
- ^ Reference, Genetics Home. "NDUFAF1 gene". Genetics Home Reference. Retrieved 2018-07-27.
- ^ "7 binary interactions found for search term FOXRED1". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-08-25.
Further reading
[edit]- Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
- Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S (September 2000). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Reports. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
- Lehner B, Sanderson CM (July 2004). "A protein interaction framework for human mRNA degradation". Genome Research. 14 (7): 1315–23. doi:10.1101/gr.2122004. PMC 442147. PMID 15231747.
- Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A (October 2004). "From ORFeome to biology: a functional genomics pipeline". Genome Research. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
- Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S (January 2006). "The LIFEdb database in 2006". Nucleic Acids Research. 34 (Database issue): D415-8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.