{{Short description|Protein-coding gene in the species Homo sapiens}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox_gene}} '''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.<ref name="entrez">{{cite web | title = Entrez Gene: FOXRED1 FAD-dependent oxidoreductase domain containing 1 | url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=55572 }}</ref><ref name="Oh_1999">{{cite journal | vauthors = Oh JJ, Grosshans DR, Wong SG, Slamon DJ | title = Identification of differentially expressed genes associated with HER-2/neu overexpression in human breast cancer cells | journal = Nucleic Acids Research | volume = 27 | issue = 20 | pages = 4008–4017 | date = October 1999 | pmid = 10497265 | pmc = 148668 | doi = 10.1093/nar/27.20.4008 }}</ref> 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.<ref name="Voet_2013">{{cite book | vauthors = Voet D, Voet JG, Pratt CW | chapter = 18 | title = Fundamentals of biochemistry: life at the molecular level | location = Hoboken, NJ | pages = 581–620 | date = 2013 | publisher = Wiley | isbn = 978-0-470-54784-7 | edition = 4th }}</ref><ref name="Fassone_2010">{{cite journal | vauthors = 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 | title = FOXRED1, encoding an FAD-dependent oxidoreductase complex-I-specific molecular chaperone, is mutated in infantile-onset mitochondrial encephalopathy | journal = Human Molecular Genetics | volume = 19 | issue = 24 | pages = 4837–4847 | date = December 2010 | pmid = 20858599 | pmc = 4560042 | doi = 10.1093/hmg/ddq414 }}</ref><ref name="cite3e7cb402">{{Cite web | title = FOXRED1 - FAD-dependent oxidoreductase domain-containing protein 1 - Homo sapiens (Human) - FOXRED1 gene & protein | url = https://www.uniprot.org/uniprot/Q96CU9 | website = uniprot.org | access-date = 2018-07-27 }}</ref> Mutations in ''FOXRED1'' have been associated with Leigh syndrome<ref name="Formosa_2015">{{cite journal | vauthors = Formosa LE, Mimaki M, Frazier AE, McKenzie M, Stait TL, Thorburn DR, Stroud DA, Ryan MT | title = Characterization of mitochondrial FOXRED1 in the assembly of respiratory chain complex I | journal = Human Molecular Genetics | volume = 24 | issue = 10 | pages = 2952–2965 | date = May 2015 | pmid = 25678554 | doi = 10.1093/hmg/ddv058 | hdl-access = free | doi-access = free | hdl = 10536/DRO/DU:30112237 }}</ref><ref name="Calvo_2010">{{cite journal | vauthors = 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 | title = High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency | journal = Nature Genetics | volume = 42 | issue = 10 | pages = 851–858 | date = October 2010 | pmid = 20818383 | pmc = 2977978 | doi = 10.1038/ng.659 }}</ref> and infantile-onset mitochondrial encephalopathy.<ref name="Fassone_2010" />
== Structure == ''FOXRED1'' is located on the q arm of chromosome 11 in position 14.2 and has 12 exons.<ref name="entrez" /> The ''FOXRED1'' gene produces a 53.8 kDa protein composed of 486 amino acids.<ref>{{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 | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–1053 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}</ref><ref>{{Cite web | vauthors = Yao D | title = Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information | url = https://amino.heartproteome.org/web/protein/Q96CU9 | website = amino.heartproteome.org | access-date = 2018-07-27 }}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> Alternatively spliced transcript variants have been observed for this gene.<ref name="entrez" />
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 pyruvate 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.<ref name="Fassone_2010" /><ref name="Formosa_2015" /> 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.<ref name="Formosa_2015" /> 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.<ref name="Fassone_2010" />
== Function ==
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.<ref name="entrez" /><ref name="Formosa_2015" /> 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.<ref>{{Cite web | vauthors = Reference GH | title = NDUFAF1 gene | url = https://ghr.nlm.nih.gov/gene/NDUFAF1 | archive-url = https://web.archive.org/web/20170216233257/https://ghr.nlm.nih.gov/gene/NDUFAF1 | url-status = dead | archive-date = February 16, 2017 | website = Genetics Home Reference | language = en | access-date = 2018-07-27 }}</ref> 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.<ref name="Formosa_2015" />
== Clinical Significance == 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.<ref name="cite3e7cb402" /> 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<ref name="Formosa_2015" /><ref name="Calvo_2010" /> and infantile-onset mitochondrial encephalopathy.<ref name="Fassone_2010" /> 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.<ref name="Formosa_2015" />
== Interactions == 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.<ref name="Formosa_2015" /> In addition to co-complexes and potential associations, FOXRED1 has been confirmed to have protein-protein interactions with EXOSC10.<ref>{{cite web | title = 7 binary interactions found for search term FOXRED1 | url = https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=FOXRED1 | work = IntAct Molecular Interaction Database | publisher = EMBL-EBI | access-date = 2018-08-25 }}</ref>
== References == {{reflist}}
== Further reading == {{refbegin | 2}} * {{cite journal | vauthors = Hartley JL, Temple GF, Brasch MA | title = DNA cloning using in vitro site-specific recombination | journal = Genome Research | volume = 10 | issue = 11 | pages = 1788–1795 | date = November 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }} * {{cite journal | vauthors = Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S | title = Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing | journal = EMBO Reports | volume = 1 | issue = 3 | pages = 287–292 | date = September 2000 | pmid = 11256614 | pmc = 1083732 | doi = 10.1093/embo-reports/kvd058 }} * {{cite journal | vauthors = Lehner B, Sanderson CM | title = A protein interaction framework for human mRNA degradation | journal = Genome Research | volume = 14 | issue = 7 | pages = 1315–1323 | date = July 2004 | pmid = 15231747 | pmc = 442147 | doi = 10.1101/gr.2122004 }} * {{cite journal | vauthors = Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A | title = From ORFeome to biology: a functional genomics pipeline | journal = Genome Research | volume = 14 | issue = 10B | pages = 2136–2144 | date = October 2004 | pmid = 15489336 | pmc = 528930 | doi = 10.1101/gr.2576704 }} * {{cite journal | vauthors = 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 | title = The LIFEdb database in 2006 | journal = Nucleic Acids Research | volume = 34 | issue = Database issue | pages = D415–D418 | date = January 2006 | pmid = 16381901 | pmc = 1347501 | doi = 10.1093/nar/gkj139 }} {{refend}}
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