ID   PEO1_MOUSE              Reviewed;         685 AA.
AC   Q8CIW5; Q8K1Z1;
DT   25-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-MAR-2003, sequence version 1.
DT   27-MAR-2024, entry version 145.
DE   RecName: Full=Twinkle mtDNA helicase {ECO:0000312|MGI:MGI:2137410};
DE            EC=5.6.2.3 {ECO:0000250|UniProtKB:Q96RR1};
DE   AltName: Full=Progressive external ophthalmoplegia 1 protein homolog;
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|MGI:MGI:2137410}; Synonyms=Peo1;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC   TISSUE=Fibroblast;
RA   Spelbrink J.N.;
RT   "Cloning of full length Mus musculus Twinkle cDNA.";
RL   Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   STRAIN=BALB/cJ;
RX   PubMed=16141072; DOI=10.1126/science.1112014;
RA   Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA   Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA   Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA   Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA   Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA   Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA   Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA   Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA   Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA   Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA   Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA   Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA   Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA   Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA   Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA   Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA   Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA   Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA   Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA   Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA   Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA   Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA   Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA   Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA   Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA   van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA   Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA   Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA   Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA   Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA   Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA   Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA   Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA   Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT   "The transcriptional landscape of the mammalian genome.";
RL   Science 309:1559-1563(2005).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC   STRAIN=FVB/N; TISSUE=Liver;
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   [4]
RP   TISSUE SPECIFICITY, COREGULATION WITH MRPL43, AND FUNCTION.
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).
CC   -!- FUNCTION: Mitochondrial helicase involved in mtDNA replication and
CC       repair (By similarity). Might have a role in mtDNA repair (By
CC       similarity). 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       (By similarity). Preferentially unwinds DNA substrates with pre-
CC       existing 5'-and 3'- single-stranded tails but is also active on a
CC       5'- flap substrate (By similarity). Can dissociate the invading strand
CC       of immobile or mobile D-loop DNA structures irrespective of the single
CC       strand polarity of the third strand (By similarity). In addition to its
CC       DNA strand separation activity, also has DNA strand annealing, DNA
CC       strand-exchange and DNA branch migration activities (By similarity).
CC       {ECO:0000250|UniProtKB:Q96RR1}.
CC   -!- CATALYTIC ACTIVITY:
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:0000250|UniProtKB:Q96RR1};
CC   -!- CATALYTIC ACTIVITY:
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:0000250|UniProtKB:Q96RR1};
CC   -!- SUBUNIT: Homohexamer (via C-terminus), which assembles in a ring-like
CC       structure (By similarity). Homoheptamer, which assembles in a ring-like
CC       structure (By similarity). Homooctamer, which assembles in a ring-like
CC       structure (By similarity). Oligomers may sequentially eject two
CC       monomers (octamer>heptamer>hexamer) upon DNA binding (By similarity).
CC       Oligomerization is Mg(2+), nucleotide and DNA-independent, however,
CC       Mg(2+) and nucleotide stabilize the homohexameric form (By similarity).
CC       Interacts with POLG in vitro. Interacts with LONP1.
CC       {ECO:0000250|UniProtKB:Q96RR1}.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion matrix, mitochondrion nucleoid
CC       {ECO:0000250|UniProtKB:Q96RR1}. Mitochondrion inner membrane
CC       {ECO:0000250|UniProtKB:Q96RR1}; Peripheral membrane protein
CC       {ECO:0000250|UniProtKB:Q96RR1}. Note=Colocalizes with mtDNA in
CC       mitochondrial nucleoids, a nucleoproteins complex consisting of a
CC       number of copies of proteins associated with mtDNA, probably involved
CC       in mtDNA maintenance and expression (By similarity). Associates with
CC       phospholipid membranes via electrostatic binding (By similarity).
CC       Preferentially associates with membranes enriched with cardiolipin, a
CC       lipid abundant in the mitochondrial inner membrane (By similarity).
CC       ATPase and helicase activity is enhanced by binding to lipid membranes
CC       (By similarity). {ECO:0000250|UniProtKB:Q96RR1,
CC       ECO:0000250|UniProtKB:Q9VL76}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q8CIW5-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q8CIW5-2; Sequence=VSP_015962, VSP_015963;
CC   -!- TISSUE SPECIFICITY: Ubiquitous with the highest levels in the liver,
CC       heart and kidneys. The skeletal muscle, brain and testis showed lower
CC       but detectable expression. Expression is coregulated with MRPL43.
CC       {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:0000250|UniProtKB:Q96RR1}.
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:0000250|UniProtKB:Q96RR1}.
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DR   EMBL; AY059385; AAL27647.1; -; mRNA.
DR   EMBL; AK146244; BAE27008.1; -; mRNA.
DR   EMBL; BC034909; AAH34909.1; -; mRNA.
DR   EMBL; BC071195; AAH71195.1; -; mRNA.
DR   CCDS; CCDS29854.1; -. [Q8CIW5-1]
DR   RefSeq; NP_001335188.1; NM_001348259.1. [Q8CIW5-2]
DR   RefSeq; NP_722491.2; NM_153796.4. [Q8CIW5-1]
DR   AlphaFoldDB; Q8CIW5; -.
DR   SMR; Q8CIW5; -.
DR   BioGRID; 230482; 2.
DR   STRING; 10090.ENSMUSP00000026227; -.
DR   iPTMnet; Q8CIW5; -.
DR   PhosphoSitePlus; Q8CIW5; -.
DR   EPD; Q8CIW5; -.
DR   MaxQB; Q8CIW5; -.
DR   PaxDb; 10090-ENSMUSP00000026227; -.
DR   PeptideAtlas; Q8CIW5; -.
DR   ProteomicsDB; 301789; -. [Q8CIW5-1]
DR   ProteomicsDB; 301790; -. [Q8CIW5-2]
DR   Pumba; Q8CIW5; -.
DR   Antibodypedia; 1261; 257 antibodies from 25 providers.
DR   Ensembl; ENSMUST00000026227.3; ENSMUSP00000026227.3; ENSMUSG00000025209.6. [Q8CIW5-1]
DR   GeneID; 226153; -.
DR   KEGG; mmu:226153; -.
DR   UCSC; uc008hqh.1; mouse. [Q8CIW5-2]
DR   UCSC; uc008hqi.1; mouse. [Q8CIW5-1]
DR   AGR; MGI:2137410; -.
DR   MGI; MGI:2137410; Twnk.
DR   VEuPathDB; HostDB:ENSMUSG00000025209; -.
DR   eggNOG; KOG2373; Eukaryota.
DR   GeneTree; ENSGT00390000004495; -.
DR   HOGENOM; CLU_012336_1_0_1; -.
DR   InParanoid; Q8CIW5; -.
DR   OMA; WFSPGGL; -.
DR   OrthoDB; 9502at2759; -.
DR   PhylomeDB; Q8CIW5; -.
DR   TreeFam; TF105994; -.
DR   BRENDA; 3.6.4.12; 3474.
DR   BioGRID-ORCS; 226153; 27 hits in 83 CRISPR screens.
DR   ChiTaRS; Twnk; mouse.
DR   PRO; PR:Q8CIW5; -.
DR   Proteomes; UP000000589; Chromosome 19.
DR   RNAct; Q8CIW5; Protein.
DR   Bgee; ENSMUSG00000025209; Expressed in epiblast (generic) and 183 other cell types or tissues.
DR   ExpressionAtlas; Q8CIW5; baseline and differential.
DR   GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0042645; C:mitochondrial nucleoid; ISS:UniProtKB.
DR   GO; GO:0005739; C:mitochondrion; IDA:MGI.
DR   GO; GO:0043139; F:5'-3' DNA helicase activity; ISS:UniProtKB.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0016887; F:ATP hydrolysis activity; ISO:MGI.
DR   GO; GO:0003678; F:DNA helicase activity; IDA:MGI.
DR   GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR   GO; GO:0016853; F:isomerase activity; IEA:UniProtKB-KW.
DR   GO; GO:0008289; F:lipid binding; ISO:MGI.
DR   GO; GO:0002020; F:protease binding; ISO:MGI.
DR   GO; GO:0003697; F:single-stranded DNA binding; ISS: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:MGI.
DR   GO; GO:0006264; P:mitochondrial DNA replication; IMP:UniProtKB.
DR   GO; GO:0006390; P:mitochondrial transcription; ISO:MGI.
DR   GO; GO:0034214; P:protein hexamerization; ISO:MGI.
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.
DR   Genevisible; Q8CIW5; MM.
PE   2: Evidence at transcript level;
KW   Alternative splicing; ATP-binding; Coiled coil; DNA replication; Helicase;
KW   Hydrolase; Isomerase; Lipid-binding; Membrane; Mitochondrion;
KW   Mitochondrion inner membrane; Mitochondrion nucleoid; Nucleotide-binding;
KW   Reference proteome; Transit peptide.
FT   TRANSIT         1..31
FT                   /note="Mitochondrion"
FT                   /evidence="ECO:0000250"
FT   CHAIN           32..685
FT                   /note="Twinkle mtDNA helicase"
FT                   /id="PRO_0000042641"
FT   DOMAIN          385..636
FT                   /note="SF4 helicase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00596"
FT   REGION          1..122
FT                   /note="Contributes to single strand DNA binding activity"
FT                   /evidence="ECO:0000250|UniProtKB:Q96RR1"
FT   REGION          54..214
FT                   /note="N-terminal region (NTR)"
FT                   /evidence="ECO:0000250|UniProtKB:Q96RR1"
FT   REGION          122..373
FT                   /note="Required for hexamers formation and DNA helicase
FT                   activity"
FT                   /evidence="ECO:0000250|UniProtKB:Q96RR1"
FT   REGION          215..335
FT                   /note="Primase-like domain"
FT                   /evidence="ECO:0000250|UniProtKB:Q96RR1"
FT   REGION          406..591
FT                   /note="Maybe required for stable oligomeric structure"
FT                   /evidence="ECO:0000250|UniProtKB:Q96RR1"
FT   REGION          641..685
FT                   /note="Might negatively regulate ATPase activity"
FT                   /evidence="ECO:0000250|UniProtKB:Q96RR1"
FT   REGION          642..685
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COILED          454..482
FT                   /evidence="ECO:0000255"
FT   BINDING         416..423
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00596"
FT   VAR_SEQ         1..398
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_015962"
FT   VAR_SEQ         399..415
FT                   /note="LNRLLKGHRKGELTVFT -> MCCQTLLLTQSFVRPPI (in isoform
FT                   2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_015963"
SQ   SEQUENCE   685 AA;  76993 MW;  F9CF69BDC4DCF838 CRC64;
     MWLLLRRAYP LRILLPLRGE WVGRRGLPRS LAPGPPRRRY RKEALPALEM PVSPVTTTEI
     RQYLRAHGIP FQDGHSCLRA PSPFVVSSDI KNEKKDAPTS FCLFIDKTTG HFLCMTSLAE
     GSWEDLQASV EGRGDGAKEG VLLREGPEAE VREEVLRIWN RAIPLWELPD PEEAQLARVM
     FGLTKVTDDT LRRFSVRYLR SARSLVFPWF TPGSSGLRGL KLLGAEGQEN GVQYVETTIP
     RPGVYHNLFG LPLISRRDTE VVVTSRELDS LALSQSTGLP TLSLPRGTVC LPPALLPYLE
     QFRRIVFWLG DDLRSWEAAK LFARKLNPKR CSLVRPGNQQ PRPLEALNQG LSLPRILRTA
     LPAWHKSIVS FRQLREEVLG ELSNVEQAAG VRWSRFPDLN RLLKGHRKGE LTVFTGPTGS
     GKTTFISEYA LDLCTQGVNT LWGSFEISNV RLARVMLTQF AVTRLEEQLD KYEEWADRFE
     DLPLYFMTFH GQQSIRSVID TMQHAVYVYD VCHVVIDNLQ FMMGHEQLSS DRIAAQDYIV
     GAFRKFATDN SCHVTLVIHP RKEDDDKELQ TASIFGSAKA SQEADNVLIL QDRKLVTGPG
     KRYLQVSKNR FDGDVGVFPL EFNKNSLTFS IPPKSKARLK KIKDDNGLVA KKSSSGKKGA
     AHQNPEICLG QDPSPAQPDT SKSSG
//