ID PEO1_HUMAN Reviewed; 684 AA.
AC Q96RR1; B2CQL2; Q6MZX2; Q6PJP5; Q96RR0;
DT 25-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 27-MAR-2024, entry version 185.
DE RecName: Full=Twinkle mtDNA helicase {ECO:0000312|HGNC:HGNC:1160};
DE EC=5.6.2.3 {ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:17324440, ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949, ECO:0000269|PubMed:27226550};
DE AltName: Full=Progressive external ophthalmoplegia 1 protein;
DE AltName: Full=T7 gp4-like protein with intramitochondrial nucleoid localization;
DE AltName: Full=T7-like mitochondrial DNA helicase;
DE AltName: Full=Twinkle protein, mitochondrial {ECO:0000305};
DE Flags: Precursor;
GN Name=TWNK {ECO:0000312|HGNC:HGNC:1160}; Synonyms=C10orf2, PEO1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY,
RP SUBCELLULAR LOCATION, VARIANT ILE-368, AND VARIANTS PEOA3 LEU-315; PRO-354;
RP THR-359; THR-367; PRO-369; GLN-374; PRO-381; CYS-474 AND PRO-475.
RX PubMed=11431692; DOI=10.1038/90058;
RA Spelbrink J.N., Li F.-Y., Tiranti V., Nikali K., Yuan Q.-P., Tariq M.,
RA Wanrooij S., Garrido N., Comi G., Morandi L., Santoro L., Toscano A.,
RA Fabrizi G.-M., Somer H., Croxen R., Beeson D., Poulton J., Suomalainen A.,
RA Jacobs H.T., Zeviani M., Larsson C.;
RT "Human mitochondrial DNA deletions associated with mutations in the gene
RT for Twinkle, a phage T7 gene 4-like protein localized in mitochondria.";
RL Nat. Genet. 28:223-231(2001).
RN [2]
RP ERRATUM OF PUBMED:11431692.
RA Spelbrink J.N., Li F.-Y., Tiranti V., Nikali K., Yuan Q.-P., Tariq M.,
RA Wanrooij S., Garrido N., Comi G., Morandi L., Santoro L., Toscano A.,
RA Fabrizi G.-M., Somer H., Croxen R., Beeson D., Poulton J., Suomalainen A.,
RA Jacobs H.T., Zeviani M., Larsson C.;
RL Nat. Genet. 29:100-100(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Fetal brain;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-348; ILE-368 AND
RP LYS-634.
RG NIEHS SNPs program;
RL Submitted (MAR-2008) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 132-582 (ISOFORM 2).
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP FUNCTION (ISOFORM 1), AND CATALYTIC ACTIVITY (ISOFORM 1).
RX PubMed=12975372; DOI=10.1074/jbc.m306981200;
RA Korhonen J.A., Gaspari M., Falkenberg M.;
RT "TWINKLE has 5' -> 3' DNA helicase activity and is specifically stimulated
RT by mitochondrial single-stranded DNA-binding protein.";
RL J. Biol. Chem. 278:48627-48632(2003).
RN [9]
RP FUNCTION (ISOFORM 1), AND INTERACTION WITH POLG (ISOFORM 1).
RX PubMed=15167897; DOI=10.1038/sj.emboj.7600257;
RA Korhonen J.A., Pham X.H., Pellegrini M., Falkenberg M.;
RT "Reconstitution of a minimal mtDNA replisome in vitro.";
RL EMBO J. 23:2423-2429(2004).
RN [10]
RP TISSUE SPECIFICITY, AND COREGULATION WITH MRPL43.
RX PubMed=15509589; DOI=10.1093/hmg/ddh342;
RA Tyynismaa H., Sembongi H., Bokori-Brown M., Granycome C., Ashley N.,
RA Poulton J., Jalanko A., Spelbrink J.N., Holt I.J., Suomalainen A.;
RT "Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA
RT copy number.";
RL Hum. Mol. Genet. 13:3219-3227(2004).
RN [11]
RP INTERACTION WITH LONP1.
RX PubMed=14739292; DOI=10.1074/jbc.m309642200;
RA Liu T., Lu B., Lee I., Ondrovicova G., Kutejova E., Suzuki C.K.;
RT "DNA and RNA binding by the mitochondrial lon protease is regulated by
RT nucleotide and protein substrate.";
RL J. Biol. Chem. 279:13902-13910(2004).
RN [12]
RP POSSIBLE MECHANISM OF DELETION FORMATION.
RX PubMed=15181170; DOI=10.1093/nar/gkh634;
RA Wanrooij S., Luoma P., van Goethem G., van Broeckhoven C., Suomalainen A.,
RA Spelbrink J.N.;
RT "Twinkle and POLG defects enhance age-dependent accumulation of mutations
RT in the control region of mtDNA.";
RL Nucleic Acids Res. 32:3053-3064(2004).
RN [13]
RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), AND SUBUNIT (ISOFORM
RP 1).
RX PubMed=17324440; DOI=10.1016/j.jmb.2007.01.079;
RA Ziebarth T.D., Farr C.L., Kaguni L.S.;
RT "Modular architecture of the hexameric human mitochondrial DNA helicase.";
RL J. Mol. Biol. 367:1382-1391(2007).
RN [14]
RP FUNCTION (ISOFORMS 1 AND 2), CATALYTIC ACTIVITY (ISOFORM 1), SUBUNIT
RP (ISOFORMS 1 AND 2), AND DOMAIN.
RX PubMed=18039713; DOI=10.1093/nar/gkm1025;
RA Farge G., Holmlund T., Khvorostova J., Rofougaran R., Hofer A.,
RA Falkenberg M.;
RT "The N-terminal domain of TWINKLE contributes to single-stranded DNA
RT binding and DNA helicase activities.";
RL Nucleic Acids Res. 36:393-403(2008).
RN [15]
RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), SUBUNIT (ISOFORM 1),
RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS LEU-315; GLU-319;
RP THR-359; PRO-369; GLN-374 AND CYS-474.
RX PubMed=18971204; DOI=10.1093/hmg/ddn359;
RA Goffart S., Cooper H.M., Tyynismaa H., Wanrooij S., Suomalainen A.,
RA Spelbrink J.N.;
RT "Twinkle mutations associated with autosomal dominant progressive external
RT ophthalmoplegia lead to impaired helicase function and in vivo mtDNA
RT replication stalling.";
RL Hum. Mol. Genet. 18:328-340(2009).
RN [16]
RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), ACTIVITY REGULATION
RP (ISOFORM 1), BIOPHYSICOCHEMICAL PROPERTIES (ISOFORM 1), SUBUNIT (ISOFORM
RP 1), AND MUTAGENESIS OF LYS-421.
RX PubMed=22383523; DOI=10.1074/jbc.m111.309468;
RA Sen D., Nandakumar D., Tang G.Q., Patel S.S.;
RT "Human mitochondrial DNA helicase TWINKLE is both an unwinding and
RT annealing helicase.";
RL J. Biol. Chem. 287:14545-14556(2012).
RN [17]
RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), AND SUBUNIT (ISOFORM
RP 1).
RX PubMed=25824949; DOI=10.1093/nar/gkv189;
RA Fernandez-Millan P., Lazaro M., Cansiz-Arda S., Gerhold J.M., Rajala N.,
RA Schmitz C.A., Silva-Espina C., Gil D., Bernado P., Valle M.,
RA Spelbrink J.N., Sola M.;
RT "The hexameric structure of the human mitochondrial replicative helicase
RT Twinkle.";
RL Nucleic Acids Res. 43:4284-4295(2015).
RN [18]
RP FUNCTION (ISOFORM 1).
RX PubMed=26887820; DOI=10.1093/nar/gkw098;
RA Sen D., Patel G., Patel S.S.;
RT "Homologous DNA strand exchange activity of the human mitochondrial DNA
RT helicase TWINKLE.";
RL Nucleic Acids Res. 44:4200-4210(2016).
RN [19]
RP FUNCTION (ISOFORM 1), AND CATALYTIC ACTIVITY (ISOFORM 1).
RX PubMed=27226550; DOI=10.1074/jbc.m115.712026;
RA Khan I., Crouch J.D., Bharti S.K., Sommers J.A., Carney S.M.,
RA Yakubovskaya E., Garcia-Diaz M., Trakselis M.A., Brosh R.M. Jr.;
RT "Biochemical Characterization of the Human Mitochondrial Replicative
RT Twinkle Helicase: SUBSTRATE SPECIFICITY, DNA BRANCH MIGRATION, AND ABILITY
RT TO OVERCOME BLOCKADES TO DNA UNWINDING.";
RL J. Biol. Chem. 291:14324-14339(2016).
RN [20]
RP SUBUNIT (ISOFORM 1), AND CHARACTERIZATION OF PEOA3 LEU-314; GLN-334;
RP LEU-335; PRO-369 AND PRO-381.
RX PubMed=30496414; DOI=10.1093/hmg/ddy415;
RA Peter B., Farge G., Pardo-Hernandez C., Taangefjord S., Falkenberg M.;
RT "Structural basis for adPEO-causing mutations in the mitochondrial TWINKLE
RT helicase.";
RL Hum. Mol. Genet. 28:1090-1099(2019).
RN [21]
RP SUBCELLULAR LOCATION.
RX PubMed=34950192; DOI=10.3389/fgene.2021.790521;
RA So M., Stiban J., Ciesielski G.L., Hovde S.L., Kaguni L.S.;
RT "Implications of Membrane Binding by the Fe-S Cluster-Containing N-Terminal
RT Domain in the Drosophila Mitochondrial Replicative DNA Helicase.";
RL Front. Genet. 12:790521-790521(2021).
RN [22] {ECO:0007744|PDB:7T8B, ECO:0007744|PDB:7T8C}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.8 ANGSTROMS) OF 1-684 OF VARIANT
RP LEU-315, CATALYTIC ACTIVITY, SUBUNIT, AND CHARACTERIZATION OF VARIANT
RP LEU-315.
RX PubMed=35914129; DOI=10.1073/pnas.2207459119;
RA Riccio A.A., Bouvette J., Perera L., Longley M.J., Krahn J.M.,
RA Williams J.G., Dutcher R., Borgnia M.J., Copeland W.C.;
RT "Structural insight and characterization of human Twinkle helicase in
RT mitochondrial disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 119:e2207459119-e2207459119(2022).
RN [23]
RP VARIANTS PEOA3 LEU-335 AND TYR-369.
RX PubMed=12163192; DOI=10.1016/s0022-510x(02)00190-9;
RA Lewis S., Hutchison W., Thyagarajan D., Dahl H.-H.M.;
RT "Clinical and molecular features of adPEO due to mutations in the Twinkle
RT gene.";
RL J. Neurol. Sci. 201:39-44(2002).
RN [24]
RP VARIANT ILE-368.
RX PubMed=12557300; DOI=10.1002/ana.10430;
RA Arenas J., Briem E., Dahl H.-H.M., Hutchison W., Lewis S., Martin M.A.,
RA Spelbrink H., Tiranti V., Jacobs H., Zeviani M.;
RT "The V368I mutation in Twinkle does not segregate with AdPEO.";
RL Ann. Neurol. 53:278-278(2003).
RN [25]
RP VARIANT PEO GLN-334.
RX PubMed=12872260; DOI=10.1002/humu.10246;
RA Van Goethem G., Loefgren A., Dermaut B., Ceuterick C., Martin J.-J.,
RA Van Broeckhoven C.;
RT "Digenic progressive external ophthalmoplegia in a sporadic patient:
RT recessive mutations in POLG and C10orf2/Twinkle.";
RL Hum. Mutat. 22:175-176(2003).
RN [26]
RP VARIANTS PEO TRP-303 AND GLN-334.
RX PubMed=12707443; DOI=10.1212/01.wnl.0000056088.09408.3c;
RA Agostino A., Valletta L., Chinnery P.F., Ferrari G., Carrara F.,
RA Taylor R.W., Schaefer A.M., Turnbull D.M., Tiranti V., Zeviani M.;
RT "Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external
RT ophthalmoplegia (PEO).";
RL Neurology 60:1354-1356(2003).
RN [27]
RP VARIANT PEOA3 THR-319.
RX PubMed=12921794; DOI=10.1016/s0960-8966(03)00071-3;
RA Deschauer M., Kiefer R., Blakely E.L., He L., Zierz S., Turnbull D.M.,
RA Taylor R.W.;
RT "A novel Twinkle gene mutation in autosomal dominant progressive external
RT ophthalmoplegia.";
RL Neuromuscul. Disord. 13:568-572(2003).
RN [28]
RP VARIANT MTDPS7 CYS-508.
RX PubMed=16135556; DOI=10.1093/hmg/ddi328;
RA Nikali K., Suomalainen A., Saharinen J., Kuokkanen M., Spelbrink J.N.,
RA Loennqvist T., Peltonen L.;
RT "Infantile onset spinocerebellar ataxia is caused by recessive mutations in
RT mitochondrial proteins Twinkle and Twinky.";
RL Hum. Mol. Genet. 14:2981-2990(2005).
RN [29]
RP VARIANT PEOA3 GLU-319.
RX PubMed=15668446; DOI=10.1212/01.wnl.0000149767.51152.83;
RA Hudson G., Deschauer M., Busse K., Zierz S., Chinnery P.F.;
RT "Sensory ataxic neuropathy due to a novel C10Orf2 mutation with probable
RT germline mosaicism.";
RL Neurology 64:371-373(2005).
RN [30]
RP VARIANT PEOA3 GLN-374, AND VARIANT ILE-368.
RX PubMed=16639411; DOI=10.1038/sj.ejhg.5201627;
RA Naiemi M., Bannwarth S., Procaccio V., Pouget J., Desnuelle C.,
RA Pellissier J.-F., Roetig A., Munnich A., Calvas P., Richelme C.,
RA Jonveaux P., Castelnovo G., Simon M., Clanet M., Wallace D.,
RA Paquis-Flucklinger V.;
RT "Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple
RT deletions or depletion of mitochondrial DNA by a dHPLC-based assay.";
RL Eur. J. Hum. Genet. 14:917-922(2006).
RN [31]
RP VARIANT MTDPS7 ILE-457, AND CHARACTERIZATION OF VARIANT MTDPS7 ILE-457.
RX PubMed=17722119; DOI=10.1002/ana.21207;
RA Sarzi E., Goffart S., Serre V., Chretien D., Slama A., Munnich A.,
RA Spelbrink J.N., Roetig A.;
RT "Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA
RT depletion.";
RL Ann. Neurol. 62:579-587(2007).
RN [32]
RP VARIANTS MTDPS7 THR-318 AND CYS-508.
RX PubMed=17921179; DOI=10.1093/brain/awm242;
RA Hakonen A.H., Isohanni P., Paetau A., Herva R., Suomalainen A.,
RA Lonnqvist T.;
RT "Recessive Twinkle mutations in early onset encephalopathy with mtDNA
RT depletion.";
RL Brain 130:3032-3040(2007).
RN [33]
RP VARIANT PEOA3 PRO-357.
RX PubMed=17614277; DOI=10.1016/j.nmd.2007.05.006;
RA Rivera H., Blazquez A., Carretero J., Alvarez-Cermeno J.C., Campos Y.,
RA Cabello A., Gonzalez-Vioque E., Borstein B., Garesse R., Arenas J.,
RA Martin M.A.;
RT "Mild ocular myopathy associated with a novel mutation in mitochondrial
RT twinkle helicase.";
RL Neuromuscul. Disord. 17:677-680(2007).
RN [34]
RP VARIANTS PEOA3 TRP-303; SER-315; PRO-334; ASN-426; SER-474; ILE-478 AND
RP LYS-479.
RX PubMed=18575922; DOI=10.1007/s00415-008-0926-3;
RA Virgilio R., Ronchi D., Hadjigeorgiou G.M., Bordoni A., Saladino F.,
RA Moggio M., Adobbati L., Kafetsouli D., Tsironi E., Previtali S.,
RA Papadimitriou A., Bresolin N., Comi G.P.;
RT "Novel Twinkle (PEO1) gene mutations in Mendelian progressive external
RT ophthalmoplegia.";
RL J. Neurol. 255:1384-1391(2008).
RN [35]
RP VARIANT PEOA3 LEU-370.
RX PubMed=18396044; DOI=10.1016/j.nmd.2007.10.007;
RA Jeppesen T.D., Schwartz M., Colding-Jorgensen E., Krag T., Hauerslev S.,
RA Vissing J.;
RT "Phenotype and clinical course in a family with a new de novo Twinkle gene
RT mutation.";
RL Neuromuscul. Disord. 18:306-309(2008).
RN [36]
RP VARIANT PEOA3 GLN-303.
RX PubMed=19353676; DOI=10.1002/ajmg.a.32731;
RA Van Hove J.L., Cunningham V., Rice C., Ringel S.P., Zhang Q., Chou P.C.,
RA Truong C.K., Wong L.J.;
RT "Finding twinkle in the eyes of a 71-year-old lady: a case report and
RT review of the genotypic and phenotypic spectrum of TWINKLE-related dominant
RT disease.";
RL Am. J. Med. Genet. A 149:861-867(2009).
RN [37]
RP VARIANT PEOA3 TRP-303.
RX PubMed=19428252; DOI=10.1016/j.nmd.2009.04.008;
RA Negro R., Zoccolella S., Dell'aglio R., Amati A., Artuso L., Bisceglia L.,
RA Lavolpe V., Papa S., Serlenga L., Petruzzella V.;
RT "Molecular analysis in a family presenting with a mild form of late-onset
RT autosomal dominant chronic progressive external ophthalmoplegia.";
RL Neuromuscul. Disord. 19:423-426(2009).
RN [38]
RP VARIANT MTDPS7 GLY-360.
RX PubMed=19853444; DOI=10.1016/j.nmd.2009.10.002;
RA Bohlega S., Van Goethem G., Al Semari A., Lofgren A., Al Hamed M.,
RA Van Broeckhoven C., Kambouris M.;
RT "Novel Twinkle gene mutation in autosomal dominant progressive external
RT ophthalmoplegia and multisystem failure.";
RL Neuromuscul. Disord. 19:845-848(2009).
RN [39]
RP VARIANTS PEOA3 GLN-303; TRP-303; GLN-334; PRO-354; PRO-357; THR-359;
RP PRO-362; LEU-363; CYS-370; GLN-374; PRO-381; HIS-458; PRO-460; ASP-475 AND
RP LYS-479.
RX PubMed=20479361; DOI=10.1212/wnl.0b013e3181df099f;
RA Fratter C., Gorman G.S., Stewart J.D., Buddles M., Smith C., Evans J.,
RA Seller A., Poulton J., Roberts M., Hanna M.G., Rahman S., Omer S.E.,
RA Klopstock T., Schoser B., Kornblum C., Czermin B., Lecky B., Blakely E.L.,
RA Craig K., Chinnery P.F., Turnbull D.M., Horvath R., Taylor R.W.;
RT "The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)-
RT linked adPEO.";
RL Neurology 74:1619-1626(2010).
RN [40]
RP VARIANT PEOA3 GLN-374.
RX PubMed=20880070; DOI=10.1111/j.1468-1331.2010.03171.x;
RA Martin-Negrier M.L., Sole G., Jardel C., Vital C., Ferrer X., Vital A.;
RT "TWINKLE gene mutation: report of a French family with an autosomal
RT dominant progressive external ophthalmoplegia and literature review.";
RL Eur. J. Neurol. 18:436-441(2011).
RN [41]
RP VARIANT MTDPS7 VAL-456.
RX PubMed=22353293; DOI=10.1016/j.pediatrneurol.2011.12.006;
RA Dundar H., Ozgul R.K., Yalnizoglu D., Erdem S., Oguz K.K., Tuncel D.,
RA Temucin C.M., Dursun A.;
RT "Identification of a novel Twinkle mutation in a family with infantile
RT onset spinocerebellar ataxia by whole exome sequencing.";
RL Pediatr. Neurol. 46:172-177(2012).
RN [42]
RP INVOLVEMENT IN PRLTS5, AND VARIANTS PRLTS5 HIS-391; GLY-441; ILE-507 AND
RP SER-585.
RX PubMed=25355836; DOI=10.1212/wnl.0000000000001036;
RA Morino H., Pierce S.B., Matsuda Y., Walsh T., Ohsawa R., Newby M.,
RA Hiraki-Kamon K., Kuramochi M., Lee M.K., Klevit R.E., Martin A.,
RA Maruyama H., King M.C., Kawakami H.;
RT "Mutations in Twinkle primase-helicase cause Perrault syndrome with
RT neurologic features.";
RL Neurology 83:2054-2061(2014).
CC -!- FUNCTION: [Isoform 1]: Mitochondrial helicase involved in mtDNA
CC replication and repair (PubMed:12975372, PubMed:15167897,
CC PubMed:17324440, PubMed:18039713, PubMed:18971204, PubMed:25824949,
CC PubMed:26887820, PubMed:27226550). Might have a role in mtDNA repair
CC (PubMed:27226550). Has DNA strand separation activity needed to form a
CC processive replication fork for leading strand synthesis which is
CC catalyzed by the formation of a replisome complex with POLG and mtSDB
CC (PubMed:12975372, PubMed:15167897, PubMed:18039713, PubMed:22383523,
CC PubMed:26887820, PubMed:27226550). Preferentially unwinds DNA
CC substrates with pre-existing 5'-and 3'- single-stranded tails but is
CC also active on a 5'- flap substrate (PubMed:12975372, PubMed:15167897,
CC PubMed:18039713, PubMed:22383523, PubMed:26887820, PubMed:27226550).
CC Can dissociate the invading strand of immobile or mobile D-loop DNA
CC structures irrespective of the single strand polarity of the third
CC strand (PubMed:27226550). In addition to its DNA strand separation
CC activity, also has DNA strand annealing, DNA strand-exchange and DNA
CC branch migration activities (PubMed:22383523, PubMed:26887820,
CC PubMed:27226550). {ECO:0000269|PubMed:12975372,
CC ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:17324440,
CC ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204,
CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949,
CC ECO:0000269|PubMed:26887820, ECO:0000269|PubMed:27226550}.
CC -!- FUNCTION: [Isoform 2]: Lack DNA unwinding and ATP hydrolysis activities
CC (PubMed:18039713). Does not bind single-stranded or double-stranded DNA
CC (PubMed:18039713). {ECO:0000269|PubMed:18039713}.
CC -!- CATALYTIC ACTIVITY: [Isoform 1]:
CC Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=5.6.2.3;
CC Evidence={ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:17324440,
CC ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204,
CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949,
CC ECO:0000269|PubMed:27226550, ECO:0000269|PubMed:35914129};
CC -!- CATALYTIC ACTIVITY: [Isoform 1]:
CC Reaction=Couples ATP hydrolysis with the unwinding of duplex DNA at the
CC replication fork by translocating in the 5'-3' direction. This
CC creates two antiparallel DNA single strands (ssDNA). The leading
CC ssDNA polymer is the template for DNA polymerase III holoenzyme which
CC synthesizes a continuous strand.; EC=5.6.2.3;
CC Evidence={ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:17324440,
CC ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204,
CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949,
CC ECO:0000269|PubMed:27226550, ECO:0000269|PubMed:35914129};
CC -!- ACTIVITY REGULATION: [Isoform 1]: Strand annealing activity is
CC inhibited by 150 mM NaCl (in vitro). {ECO:0000269|PubMed:22383523}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES: [Isoform 1]:
CC Kinetic parameters:
CC KM=1.7 mM for UTP (using ssM13mp18 as DNA substrate)
CC {ECO:0000269|PubMed:22383523};
CC KM=1.6 mM for UTP (using ssDNA as DNA substrate)
CC {ECO:0000269|PubMed:22383523};
CC KM=1.4 mM for UTP (using forked dsDNA as DNA substrate)
CC {ECO:0000269|PubMed:22383523};
CC KM=3.4 mM for UTP (using no DNA as substrate)
CC {ECO:0000269|PubMed:22383523};
CC -!- SUBUNIT: Interacts with LONP1. {ECO:0000269|PubMed:14739292}.
CC -!- SUBUNIT: [Isoform 1]: Homohexamer (via C-terminus), which assembles in
CC a ring-like structure (PubMed:18039713, PubMed:17324440,
CC PubMed:22383523, PubMed:25824949, PubMed:30496414, PubMed:18971204).
CC Homoheptamer, which assembles in a ring-like structure
CC (PubMed:25824949, PubMed:30496414, PubMed:35914129). Homooctamer, which
CC assembles in a ring-like structure (PubMed:35914129). Oligomers may
CC sequentially eject two monomers (octamer>heptamer>hexamer) upon DNA
CC binding (PubMed:35914129). Oligomerization is Mg(2+), nucleotide and
CC DNA-independent, however, Mg(2+) and nucleotide stabilize the
CC homohexameric form (PubMed:18039713). Interacts with POLG in vitro
CC (PubMed:15167897). {ECO:0000269|PubMed:15167897,
CC ECO:0000269|PubMed:17324440, ECO:0000269|PubMed:18039713,
CC ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:22383523,
CC ECO:0000269|PubMed:25824949, ECO:0000269|PubMed:30496414,
CC ECO:0000269|PubMed:35914129}.
CC -!- SUBUNIT: [Isoform 2]: Monomer (PubMed:18039713). Does not form
CC oligomers (PubMed:18039713). {ECO:0000269|PubMed:18039713}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix, mitochondrion nucleoid
CC {ECO:0000269|PubMed:11431692, ECO:0000269|PubMed:18971204}.
CC Mitochondrion inner membrane {ECO:0000303|PubMed:34950192}; Peripheral
CC membrane protein {ECO:0000269|PubMed:34950192}. Note=Colocalizes with
CC mtDNA in mitochondrial nucleoids, a nucleoproteins complex consisting
CC of a number of copies of proteins associated with mtDNA, probably
CC involved in mtDNA maintenance and expression (PubMed:11431692).
CC Associates with phospholipid membranes via electrostatic binding (By
CC similarity). Preferentially associates with membranes enriched with
CC cardiolipin, a lipid abundant in the mitochondrial inner membrane
CC (PubMed:34950192). ATPase and helicase activity is enhanced by binding
CC to lipid membranes (PubMed:34950192). {ECO:0000250|UniProtKB:Q9VL76,
CC ECO:0000269|PubMed:11431692, ECO:0000269|PubMed:34950192}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q96RR1-1; Sequence=Displayed;
CC Name=2; Synonyms=Twinky;
CC IsoId=Q96RR1-2; Sequence=VSP_015960, VSP_015961;
CC Name=3;
CC IsoId=Q96RR1-3; Sequence=VSP_015959;
CC -!- TISSUE SPECIFICITY: High relative levels in skeletal muscle, testis and
CC pancreas. Lower levels of expression in the heart, brain, placenta,
CC lung, liver, kidney, spleen, thymus, prostate, ovary, small intestine,
CC colon and leukocytes. Expression is coregulated with MRPL43.
CC {ECO:0000269|PubMed:11431692, ECO:0000269|PubMed:15509589}.
CC -!- DOMAIN: N-terminus enhances protein stability and hexamer formation,
CC which is important for DNA binding, and is required for DNA helicase
CC activity and, ultimately, for mtDNA replisome processivity.
CC {ECO:0000269|PubMed:18039713}.
CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA
CC deletions, autosomal dominant, 3 (PEOA3) [MIM:609286]: A disorder
CC characterized by progressive weakness of ocular muscles and levator
CC muscle of the upper eyelid. In a minority of cases, it is associated
CC with skeletal myopathy, which predominantly involves axial or proximal
CC muscles and which causes abnormal fatigability and even permanent
CC muscle weakness. Ragged-red fibers and atrophy are found on muscle
CC biopsy. A large proportion of chronic ophthalmoplegias are associated
CC with other symptoms, leading to a multisystemic pattern of this
CC disease. Additional symptoms are variable, and may include cataracts,
CC hearing loss, sensory axonal neuropathy, ataxia, depression,
CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:11431692,
CC ECO:0000269|PubMed:12163192, ECO:0000269|PubMed:12921794,
CC ECO:0000269|PubMed:15668446, ECO:0000269|PubMed:16639411,
CC ECO:0000269|PubMed:17614277, ECO:0000269|PubMed:18396044,
CC ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:19353676,
CC ECO:0000269|PubMed:19428252, ECO:0000269|PubMed:20479361,
CC ECO:0000269|PubMed:20880070}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Mitochondrial DNA depletion syndrome 7 (MTDPS7) [MIM:271245]:
CC A severe disease associated with mitochondrial dysfunction. Some
CC patients are affected by progressive atrophy of the cerebellum, brain
CC stem, the spinal cord, and sensory axonal neuropathy. Clinical features
CC include hypotonia, athetosis, ataxia, ophthalmoplegia, sensorineural
CC hearing deficit, sensory axonal neuropathy, epileptic encephalopathy
CC and female hypogonadism. In some individuals liver dysfunction and
CC multi-organ failure is present. {ECO:0000269|PubMed:16135556,
CC ECO:0000269|PubMed:17722119, ECO:0000269|PubMed:17921179,
CC ECO:0000269|PubMed:19853444, ECO:0000269|PubMed:22353293}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Perrault syndrome 5 (PRLTS5) [MIM:616138]: A form of Perrault
CC syndrome, a sex-influenced disorder characterized by sensorineural
CC deafness in both males and females, and ovarian dysgenesis in females.
CC Affected females have primary amenorrhea, streak gonads, and
CC infertility, whereas affected males show normal pubertal development
CC and are fertile. {ECO:0000269|PubMed:25355836}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- CAUTION: The N-terminus contains a putative primase-like domain;
CC however the absence of the zinc binding domain and other motifs
CC important for catalysis suggests that TWNK lacks primase activity.
CC {ECO:0000305|PubMed:25824949}.
CC -!- CAUTION: In vitro, can catalyze the hydrolysis of different nucleotide
CC triphosphate (NTP) substrates with different efficiency.
CC {ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:18971204,
CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949}.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/peo1/";
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DR EMBL; AF292004; AAK69558.1; -; mRNA.
DR EMBL; AF292005; AAK69559.1; -; mRNA.
DR EMBL; BX640829; CAE45905.1; -; mRNA.
DR EMBL; AL133215; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; EU543650; ACB21043.1; -; Genomic_DNA.
DR EMBL; CH471066; EAW49794.1; -; Genomic_DNA.
DR EMBL; BC013349; AAH13349.1; -; mRNA.
DR CCDS; CCDS53570.1; -. [Q96RR1-2]
DR CCDS; CCDS7506.1; -. [Q96RR1-1]
DR RefSeq; NP_001157284.1; NM_001163812.1. [Q96RR1-2]
DR RefSeq; NP_068602.2; NM_021830.4. [Q96RR1-1]
DR PDB; 7T8B; EM; 3.80 A; A/B/C/D/E/F/G/H=1-684.
DR PDB; 7T8C; EM; 4.50 A; A/B/C/D/E/F/G=1-684.
DR PDBsum; 7T8B; -.
DR PDBsum; 7T8C; -.
DR AlphaFoldDB; Q96RR1; -.
DR EMDB; EMD-25743; -.
DR EMDB; EMD-25744; -.
DR SMR; Q96RR1; -.
DR BioGRID; 121166; 138.
DR IntAct; Q96RR1; 45.
DR MINT; Q96RR1; -.
DR STRING; 9606.ENSP00000309595; -.
DR iPTMnet; Q96RR1; -.
DR PhosphoSitePlus; Q96RR1; -.
DR BioMuta; TWNK; -.
DR DMDM; 74752111; -.
DR EPD; Q96RR1; -.
DR jPOST; Q96RR1; -.
DR MassIVE; Q96RR1; -.
DR MaxQB; Q96RR1; -.
DR PaxDb; 9606-ENSP00000309595; -.
DR PeptideAtlas; Q96RR1; -.
DR ProteomicsDB; 78006; -. [Q96RR1-1]
DR ProteomicsDB; 78007; -. [Q96RR1-2]
DR ProteomicsDB; 78008; -. [Q96RR1-3]
DR Pumba; Q96RR1; -.
DR Antibodypedia; 1261; 257 antibodies from 25 providers.
DR DNASU; 56652; -.
DR Ensembl; ENST00000311916.8; ENSP00000309595.2; ENSG00000107815.10. [Q96RR1-1]
DR Ensembl; ENST00000370228.2; ENSP00000359248.1; ENSG00000107815.10. [Q96RR1-2]
DR Ensembl; ENST00000643860.1; ENSP00000494389.1; ENSG00000107815.10. [Q96RR1-3]
DR GeneID; 56652; -.
DR KEGG; hsa:56652; -.
DR MANE-Select; ENST00000311916.8; ENSP00000309595.2; NM_021830.5; NP_068602.2.
DR UCSC; uc001ksf.3; human. [Q96RR1-1]
DR AGR; HGNC:1160; -.
DR CTD; 56652; -.
DR DisGeNET; 56652; -.
DR GeneCards; TWNK; -.
DR GeneReviews; TWNK; -.
DR HGNC; HGNC:1160; TWNK.
DR HPA; ENSG00000107815; Low tissue specificity.
DR MalaCards; TWNK; -.
DR MIM; 271245; phenotype.
DR MIM; 606075; gene.
DR MIM; 609286; phenotype.
DR MIM; 616138; phenotype.
DR neXtProt; NX_Q96RR1; -.
DR OpenTargets; ENSG00000107815; -.
DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia.
DR Orphanet; 1186; Infantile-onset spinocerebellar ataxia.
DR Orphanet; 363534; Mitochondrial DNA depletion syndrome, hepatocerebrorenal form.
DR Orphanet; 642945; Perrault syndrome type 1.
DR Orphanet; 642976; Perrault syndrome type 2.
DR Orphanet; 70595; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome.
DR PharmGKB; PA162377675; -.
DR VEuPathDB; HostDB:ENSG00000107815; -.
DR eggNOG; KOG2373; Eukaryota.
DR GeneTree; ENSGT00390000004495; -.
DR HOGENOM; CLU_012336_1_0_1; -.
DR InParanoid; Q96RR1; -.
DR OMA; WFSPGGL; -.
DR OrthoDB; 9502at2759; -.
DR PhylomeDB; Q96RR1; -.
DR TreeFam; TF105994; -.
DR BRENDA; 3.6.4.12; 2681.
DR PathwayCommons; Q96RR1; -.
DR Reactome; R-HSA-2151201; Transcriptional activation of mitochondrial biogenesis.
DR SignaLink; Q96RR1; -.
DR BioGRID-ORCS; 56652; 354 hits in 1149 CRISPR screens.
DR ChiTaRS; TWNK; human.
DR GeneWiki; PEO1; -.
DR GenomeRNAi; 56652; -.
DR Pharos; Q96RR1; Tbio.
DR PRO; PR:Q96RR1; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; Q96RR1; Protein.
DR Bgee; ENSG00000107815; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 139 other cell types or tissues.
DR ExpressionAtlas; Q96RR1; baseline and differential.
DR Genevisible; Q96RR1; HS.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR GO; GO:0043139; F:5'-3' DNA helicase activity; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016887; F:ATP hydrolysis activity; IDA:FlyBase.
DR GO; GO:0003678; F:DNA helicase activity; IBA:GO_Central.
DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB.
DR GO; GO:0016853; F:isomerase activity; IEA:UniProtKB-KW.
DR GO; GO:0008289; F:lipid binding; IDA:FlyBase.
DR GO; GO:0002020; F:protease binding; IPI:UniProtKB.
DR GO; GO:0003697; F:single-stranded DNA binding; IDA:UniProtKB.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0006268; P:DNA unwinding involved in DNA replication; IDA:FlyBase.
DR GO; GO:0006264; P:mitochondrial DNA replication; IMP:UniProtKB.
DR GO; GO:0006390; P:mitochondrial transcription; IMP:UniProtKB.
DR GO; GO:0034214; P:protein hexamerization; IDA:UniProtKB.
DR CDD; cd01029; TOPRIM_primases; 1.
DR CDD; cd01122; Twinkle_C; 1.
DR Gene3D; 3.40.1360.10; -; 1.
DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1.
DR InterPro; IPR007694; DNA_helicase_DnaB-like_C.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR034154; TOPRIM_DnaG/twinkle.
DR InterPro; IPR027032; Twinkle-like.
DR PANTHER; PTHR12873; T7-LIKE MITOCHONDRIAL DNA HELICASE; 1.
DR PANTHER; PTHR12873:SF0; TWINKLE MTDNA HELICASE; 1.
DR Pfam; PF13481; AAA_25; 1.
DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1.
DR PROSITE; PS51199; SF4_HELICASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Deafness; Disease variant;
KW DNA replication; Helicase; Hydrolase; Isomerase; Lipid-binding; Membrane;
KW Mitochondrion; Mitochondrion inner membrane; Mitochondrion nucleoid;
KW Neurodegeneration; Neuropathy; Nucleotide-binding;
KW Primary mitochondrial disease; Progressive external ophthalmoplegia;
KW Reference proteome; Transit peptide.
FT TRANSIT 1..31
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 32..684
FT /note="Twinkle mtDNA helicase"
FT /id="PRO_0000042640"
FT DOMAIN 384..635
FT /note="SF4 helicase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00596"
FT REGION 1..121
FT /note="Contributes to single strand DNA binding activity"
FT /evidence="ECO:0000269|PubMed:18039713"
FT REGION 54..214
FT /note="N-terminal region (NTR)"
FT /evidence="ECO:0000269|PubMed:35914129"
FT REGION 121..372
FT /note="Required for hexamers formation and DNA helicase
FT activity"
FT /evidence="ECO:0000269|PubMed:18039713"
FT REGION 215..335
FT /note="Primase-like domain"
FT /evidence="ECO:0000269|PubMed:35914129"
FT REGION 405..590
FT /note="Maybe required for stable oligomeric structure"
FT /evidence="ECO:0000269|PubMed:17324440"
FT REGION 637..684
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 640..684
FT /note="Might negatively regulate ATPase activity"
FT /evidence="ECO:0000269|PubMed:17324440"
FT COMPBIAS 655..678
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 415..422
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00596"
FT VAR_SEQ 532..684
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:17974005"
FT /id="VSP_015959"
FT VAR_SEQ 579..582
FT /note="ASQE -> VSGL (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11431692,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_015960"
FT VAR_SEQ 583..684
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11431692,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_015961"
FT VARIANT 303
FT /note="R -> Q (in PEOA3; dbSNP:rs137852956)"
FT /evidence="ECO:0000269|PubMed:19353676,
FT ECO:0000269|PubMed:20479361"
FT /id="VAR_065102"
FT VARIANT 303
FT /note="R -> W (in PEOA3; also detected in a case showing
FT digenic inheritance; dbSNP:rs1159929268)"
FT /evidence="ECO:0000269|PubMed:12707443,
FT ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:19428252,
FT ECO:0000269|PubMed:20479361"
FT /id="VAR_023647"
FT VARIANT 315
FT /note="W -> L (in PEOA3; reduced single-strand DNA binding;
FT increased heptamer oligomerization; increased stability of
FT the closed or 'compacted' conformation; dbSNP:rs111033575)"
FT /evidence="ECO:0000269|PubMed:11431692,
FT ECO:0000269|PubMed:30496414, ECO:0000269|PubMed:35914129"
FT /id="VAR_023648"
FT VARIANT 315
FT /note="W -> S (in PEOA3; reduces helicase activity; reduced
FT single-strand DNA binding)"
FT /evidence="ECO:0000269|PubMed:18575922,
FT ECO:0000269|PubMed:18971204"
FT /id="VAR_065103"
FT VARIANT 318
FT /note="A -> T (in MTDPS7; dbSNP:rs80356542)"
FT /evidence="ECO:0000269|PubMed:17921179"
FT /id="VAR_065104"
FT VARIANT 319
FT /note="K -> E (in PEOA3; the phenotype highly overlaps with
FT sensory ataxic neuropathy dysarthria and ophthalmoparesis;
FT reduces helicase activity and single-strand DNA binding;
FT dbSNP:rs80356543)"
FT /evidence="ECO:0000269|PubMed:15668446,
FT ECO:0000269|PubMed:18971204"
FT /id="VAR_023649"
FT VARIANT 319
FT /note="K -> T (in PEOA3)"
FT /evidence="ECO:0000269|PubMed:12921794"
FT /id="VAR_023650"
FT VARIANT 334
FT /note="R -> P (in PEOA3)"
FT /evidence="ECO:0000269|PubMed:18575922"
FT /id="VAR_065105"
FT VARIANT 334
FT /note="R -> Q (in PEO; sporadic case; the patient also
FT carries the S-848 mutation in the POLG gene suggesting
FT digenic inheritance; retains hexamer and heptamer
FT formation; dbSNP:rs28937887)"
FT /evidence="ECO:0000269|PubMed:12707443,
FT ECO:0000269|PubMed:12872260, ECO:0000269|PubMed:20479361,
FT ECO:0000269|PubMed:30496414"
FT /id="VAR_023651"
FT VARIANT 335
FT /note="P -> L (in PEOA3; displays unusual oligomeric
FT forms)"
FT /evidence="ECO:0000269|PubMed:12163192,
FT ECO:0000269|PubMed:30496414"
FT /id="VAR_023652"
FT VARIANT 348
FT /note="G -> R (in dbSNP:rs62626271)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_062268"
FT VARIANT 354
FT /note="R -> P (in PEOA3; dbSNP:rs111033576)"
FT /evidence="ECO:0000269|PubMed:11431692,
FT ECO:0000269|PubMed:20479361"
FT /id="VAR_023653"
FT VARIANT 357
FT /note="R -> P (in PEOA3; dbSNP:rs758026634)"
FT /evidence="ECO:0000269|PubMed:17614277,
FT ECO:0000269|PubMed:20479361"
FT /id="VAR_065106"
FT VARIANT 359
FT /note="A -> T (in PEOA3; reduces helicase activity;
FT dbSNP:rs111033573)"
FT /evidence="ECO:0000269|PubMed:11431692,
FT ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:20479361"
FT /id="VAR_023654"
FT VARIANT 360
FT /note="L -> G (in MTDPS7; patients manifest multi-organ
FT failure; requires 2 nucleotide substitutions)"
FT /evidence="ECO:0000269|PubMed:19853444"
FT /id="VAR_065107"
FT VARIANT 362
FT /note="A -> P (in PEOA3; dbSNP:rs1554887075)"
FT /evidence="ECO:0000269|PubMed:20479361"
FT /id="VAR_065108"
FT VARIANT 363
FT /note="W -> L (in PEOA3)"
FT /evidence="ECO:0000269|PubMed:20479361"
FT /id="VAR_065109"
FT VARIANT 367
FT /note="I -> T (in PEOA3)"
FT /evidence="ECO:0000269|PubMed:11431692"
FT /id="VAR_023655"
FT VARIANT 368
FT /note="V -> I (in dbSNP:rs17113613)"
FT /evidence="ECO:0000269|PubMed:11431692,
FT ECO:0000269|PubMed:12557300, ECO:0000269|PubMed:16639411,
FT ECO:0000269|Ref.4"
FT /id="VAR_023656"
FT VARIANT 369
FT /note="S -> P (in PEOA3; reduces helicase activity;
FT increases single strand DNA affinity; reduces closed-ring
FT quaternary structure formation)"
FT /evidence="ECO:0000269|PubMed:11431692,
FT ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:30496414"
FT /id="VAR_023657"
FT VARIANT 369
FT /note="S -> Y (in PEOA3; dbSNP:rs111033579)"
FT /evidence="ECO:0000269|PubMed:12163192"
FT /id="VAR_023658"
FT VARIANT 370
FT /note="F -> C (in PEOA3)"
FT /evidence="ECO:0000269|PubMed:20479361"
FT /id="VAR_065110"
FT VARIANT 370
FT /note="F -> L (in PEOA3; dbSNP:rs863223920)"
FT /evidence="ECO:0000269|PubMed:18396044"
FT /id="VAR_065111"
FT VARIANT 374
FT /note="R -> Q (in PEOA3; reduces helicase activity and
FT alters nucleoid structure; dbSNP:rs1554887097)"
FT /evidence="ECO:0000269|PubMed:11431692,
FT ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18971204,
FT ECO:0000269|PubMed:20479361, ECO:0000269|PubMed:20880070"
FT /id="VAR_023659"
FT VARIANT 381
FT /note="L -> P (in PEOA3; reduces closed-ring quaternary
FT structure formation; dbSNP:rs111033577)"
FT /evidence="ECO:0000269|PubMed:11431692,
FT ECO:0000269|PubMed:20479361, ECO:0000269|PubMed:30496414"
FT /id="VAR_023660"
FT VARIANT 391
FT /note="R -> H (in PRLTS5; dbSNP:rs556445621)"
FT /evidence="ECO:0000269|PubMed:25355836"
FT /id="VAR_072657"
FT VARIANT 426
FT /note="S -> N (in PEOA3)"
FT /evidence="ECO:0000269|PubMed:18575922"
FT /id="VAR_065112"
FT VARIANT 427
FT /note="E -> G (in dbSNP:rs11542126)"
FT /id="VAR_051267"
FT VARIANT 441
FT /note="W -> G (in PRLTS5; dbSNP:rs672601361)"
FT /evidence="ECO:0000269|PubMed:25355836"
FT /id="VAR_072658"
FT VARIANT 456
FT /note="L -> V (in MTDPS7; infantile spinocerebellar ataxia
FT phenotype; dbSNP:rs386834145)"
FT /evidence="ECO:0000269|PubMed:22353293"
FT /id="VAR_067722"
FT VARIANT 457
FT /note="T -> I (in MTDPS7; affects helicase activity;
FT dbSNP:rs80356544)"
FT /evidence="ECO:0000269|PubMed:17722119"
FT /id="VAR_039045"
FT VARIANT 458
FT /note="Q -> H (in PEOA3; dbSNP:rs1554887213)"
FT /evidence="ECO:0000269|PubMed:20479361"
FT /id="VAR_065113"
FT VARIANT 460
FT /note="A -> P (in PEOA3)"
FT /evidence="ECO:0000269|PubMed:20479361"
FT /id="VAR_065114"
FT VARIANT 474
FT /note="W -> C (in PEOA3; reduces helicase activity and
FT alters nucleoid structure; dbSNP:rs111033574)"
FT /evidence="ECO:0000269|PubMed:11431692,
FT ECO:0000269|PubMed:18971204"
FT /id="VAR_023661"
FT VARIANT 474
FT /note="W -> S (in PEOA3; dbSNP:rs11542127)"
FT /evidence="ECO:0000269|PubMed:18575922"
FT /id="VAR_065115"
FT VARIANT 475
FT /note="A -> D (in PEOA3)"
FT /evidence="ECO:0000269|PubMed:20479361"
FT /id="VAR_065116"
FT VARIANT 475
FT /note="A -> P (in PEOA3; dbSNP:rs111033572)"
FT /evidence="ECO:0000269|PubMed:11431692"
FT /id="VAR_023662"
FT VARIANT 478
FT /note="F -> I (in PEOA3)"
FT /evidence="ECO:0000269|PubMed:18575922"
FT /id="VAR_065117"
FT VARIANT 479
FT /note="E -> K (in PEOA3; dbSNP:rs1085307937)"
FT /evidence="ECO:0000269|PubMed:18575922,
FT ECO:0000269|PubMed:20479361"
FT /id="VAR_065118"
FT VARIANT 507
FT /note="V -> I (in PRLTS5; dbSNP:rs369588002)"
FT /evidence="ECO:0000269|PubMed:25355836"
FT /id="VAR_072659"
FT VARIANT 508
FT /note="Y -> C (in MTDPS7; dbSNP:rs80356540)"
FT /evidence="ECO:0000269|PubMed:16135556,
FT ECO:0000269|PubMed:17921179"
FT /id="VAR_043797"
FT VARIANT 585
FT /note="N -> S (in PRLTS5; dbSNP:rs672601360)"
FT /evidence="ECO:0000269|PubMed:25355836"
FT /id="VAR_072660"
FT VARIANT 634
FT /note="N -> K (in dbSNP:rs62626293)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_062269"
FT MUTAGEN 421
FT /note="K->A: Loss of helicase activity on 5'-tailed
FT substrate."
FT /evidence="ECO:0000269|PubMed:22383523"
FT CONFLICT 351
FT /note="N -> D (in Ref. 3; CAE45905)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 684 AA; 77154 MW; 58186043888234DA CRC64;
MWVLLRSGYP LRILLPLRGE WMGRRGLPRN LAPGPPRRRY RKETLQALDM PVLPVTATEI
RQYLRGHGIP FQDGHSCLRA LSPFAESSQL KGQTGVTTSF SLFIDKTTGH FLCMTSLAEG
SWEDFQASVE GRGDGAREGF LLSKAPEFED SEEVRRIWNR AIPLWELPDQ EEVQLADTMF
GLTKVTDDTL KRFSVRYLRP ARSLVFPWFS PGGSGLRGLK LLEAKCQGDG VSYEETTIPR
PSAYHNLFGL PLISRRDAEV VLTSRELDSL ALNQSTGLPT LTLPRGTTCL PPALLPYLEQ
FRRIVFWLGD DLRSWEAAKL FARKLNPKRC FLVRPGDQQP RPLEALNGGF NLSRILRTAL
PAWHKSIVSF RQLREEVLGE LSNVEQAAGL RWSRFPDLNR ILKGHRKGEL TVFTGPTGSG
KTTFISEYAL DLCSQGVNTL WGSFEISNVR LARVMLTQFA EGRLEDQLDK YDHWADRFED
LPLYFMTFHG QQSIRTVIDT MQHAVYVYDI CHVIIDNLQF MMGHEQLSTD RIAAQDYIIG
VFRKFATDNN CHVTLVIHPR KEDDDKELQT ASIFGSAKAS QEADNVLILQ DRKLVTGPGK
RYLQVSKNRF DGDVGVFPLE FNKNSLTFSI PPKNKARLKK IKDDTGPVAK KPSSGKKGAT
TQNSEICSGQ APTPDQPDTS KRSK
//
