ID TIM_HUMAN Reviewed; 1208 AA. AC Q9UNS1; B2ZAV0; O94802; Q86VM1; Q8IWH3; DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 2. DT 27-MAR-2024, entry version 186. DE RecName: Full=Protein timeless homolog; DE Short=hTIM; GN Name=TIMELESS {ECO:0000312|EMBL:AAH50557.1}; GN Synonyms=TIM {ECO:0000303|PubMed:9856465}, TIM1 GN {ECO:0000303|PubMed:9891984}, TIMELESS1 {ECO:0000303|PubMed:9891984}; 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] {ECO:0000312|EMBL:BAA36499.1} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND VARIANT RP LEU-455. RC TISSUE=Brain {ECO:0000312|EMBL:BAA36499.1}; RX PubMed=9891984; DOI=10.1016/s0014-5793(98)01597-x; RA Koike N., Hida A., Numano R., Hirose M., Sakaki Y., Tei H.; RT "Identification of the mammalian homologues of the Drosophila timeless RT gene, Timeless1."; RL FEBS Lett. 441:427-431(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, TISSUE RP SPECIFICITY, AND VARIANTS LEU-455 AND GLN-831. RC TISSUE=Placenta; RX PubMed=9856465; DOI=10.1016/s0896-6273(00)80627-3; RA Sangoram A.M., Saez L., Antoch M.P., Gekakis N., Staknis D., Whiteley A., RA Fruechte E.M., Vitaterna M.H., Shimomura K., King D.P., Young M.W., RA Weitz C.J., Takahashi J.S.; RT "Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1 RT interact and negatively regulate CLOCK-ARTNL/BMAL1-induced transcription."; RL Neuron 21:1101-1113(1998). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-129; LEU-455; SER-471; RP GLN-831; VAL-870; HIS-922; TRP-924; THR-1017 AND LEU-1018. RG NIEHS SNPs program; RL Submitted (APR-2008) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16541075; DOI=10.1038/nature04569; RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., RA Gibbs R.A.; RT "The finished DNA sequence of human chromosome 12."; RL Nature 440:346-351(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANTS RP GLN-831 AND LEU-1018. RC TISSUE=Duodenum {ECO:0000312|EMBL:AAH50557.1}, and Skin RC {ECO:0000312|EMBL:AAH39842.1}; 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 [6] RP FUNCTION, INTERACTION WITH ATR; ATRIP; CHEK1 AND CRY2, AND INDUCTION. RX PubMed=15798197; DOI=10.1128/mcb.25.8.3109-3116.2005; RA Uensal-Kacmaz K., Mullen T.E., Kaufmann W.K., Sancar A.; RT "Coupling of human circadian and cell cycles by the timeless protein."; RL Mol. Cell. Biol. 25:3109-3116(2005). RN [7] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1173, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1173, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [9] RP INTERACTION WITH TIPIN. RX PubMed=17116885; DOI=10.1073/pnas.0609251103; RA Chou D.M., Elledge S.J.; RT "Tipin and Timeless form a mutually protective complex required for RT genotoxic stress resistance and checkpoint function."; RL Proc. Natl. Acad. Sci. U.S.A. 103:18143-18147(2006). RN [10] RP INTERACTION WITH TIPIN. RX PubMed=17102137; DOI=10.1074/jbc.m605596200; RA Yoshizawa-Sugata N., Masai H.; RT "Human Tim/Timeless-interacting protein, Tipin, is required for efficient RT progression of S phase and DNA replication checkpoint."; RL J. Biol. Chem. 282:2729-2740(2007). RN [11] RP SUBCELLULAR LOCATION, INTERACTION WITH CLSPN, AND FUNCTION. RX PubMed=17141802; DOI=10.1016/j.jmb.2006.10.097; RA Gotter A.L., Suppa C., Emanuel B.S.; RT "Mammalian TIMELESS and Tipin are evolutionarily conserved replication RT fork-associated factors."; RL J. Mol. Biol. 366:36-52(2007). RN [12] RP INTERACTION WITH TIPIN, AND FUNCTION. RX PubMed=17296725; DOI=10.1128/mcb.02190-06; RA Uensal-Kacmaz K., Chastain P.D., Qu P.-P., Minoo P., Cordeiro-Stone M., RA Sancar A., Kaufmann W.K.; RT "The human Tim/Tipin complex coordinates an Intra-S checkpoint response to RT UV that slows replication fork displacement."; RL Mol. Cell. Biol. 27:3131-3142(2007). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1149 AND SER-1173, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [16] RP REVIEW. RX PubMed=20139726; DOI=10.4161/cc.9.4.10676; RA McFarlane R.J., Mian S., Dalgaard J.Z.; RT "The many facets of the Tim-Tipin protein families' roles in chromosome RT biology."; RL Cell Cycle 9:700-705(2010). RN [17] RP INTERACTION WITH DDX11. RX PubMed=20124417; DOI=10.1242/jcs.057984; RA Leman A.R., Noguchi C., Lee C.Y., Noguchi E.; RT "Human Timeless and Tipin stabilize replication forks and facilitate RT sister-chromatid cohesion."; RL J. Cell Sci. 123:660-670(2010). RN [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1149 AND SER-1173, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [20] RP REVIEW. RX PubMed=21670590; DOI=10.4161/cc.10.14.15853; RA Diaz-Martinez L.A., Clarke D.J.; RT "Timeless makes some time for itself."; RL Cell Cycle 10:2254-2254(2011). RN [21] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1149 AND SER-1173, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-281; SER-1074; SER-1087; RP THR-1089; SER-1149 AND SER-1173, AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [23] RP FUNCTION. RX PubMed=23418588; DOI=10.1371/journal.pone.0056623; RA Engelen E., Janssens R.C., Yagita K., Smits V.A., van der Horst G.T., RA Tamanini F.; RT "Mammalian TIMELESS is involved in period determination and DNA damage- RT dependent phase advancing of the circadian clock."; RL PLoS ONE 8:E56623-E56623(2013). RN [24] RP FUNCTION, AND INTERACTION WITH TIPIN; MCM COMPLEX AND DNA POLYMERASES. RX PubMed=23359676; DOI=10.1073/pnas.1222494110; RA Cho W.H., Kang Y.H., An Y.Y., Tappin I., Hurwitz J., Lee J.K.; RT "Human Tim-Tipin complex affects the biochemical properties of the RT replicative DNA helicase and DNA polymerases."; RL Proc. Natl. Acad. Sci. U.S.A. 110:2523-2527(2013). RN [25] RP INTERACTION WITH DDX11. RX PubMed=26503245; DOI=10.1093/nar/gkv1112; RA Cali F., Bharti S.K., Di Perna R., Brosh R.M. Jr., Pisani F.M.; RT "Tim/Timeless, a member of the replication fork protection complex, RT operates with the Warsaw breakage syndrome DNA helicase DDX11 in the same RT fork recovery pathway."; RL Nucleic Acids Res. 44:705-717(2016). RN [26] RP FUNCTION, AND INTERACTION WITH PARP1. RX PubMed=30356214; DOI=10.1038/s41586-018-0629-6; RA Liu H., Zhang H., Wu X., Ma D., Wu J., Wang L., Jiang Y., Fei Y., Zhu C., RA Tan R., Jungblut P., Pei G., Dorhoi A., Yan Q., Zhang F., Zheng R., Liu S., RA Liang H., Liu Z., Yang H., Chen J., Wang P., Tang T., Peng W., Hu Z., RA Xu Z., Huang X., Wang J., Li H., Zhou Y., Liu F., Yan D., Kaufmann S.H.E., RA Chen C., Mao Z., Ge B.; RT "Nuclear cGAS suppresses DNA repair and promotes tumorigenesis."; RL Nature 563:131-136(2018). RN [27] RP FUNCTION. RX PubMed=35585232; DOI=10.1038/s41586-022-04759-1; RA Baris Y., Taylor M.R.G., Aria V., Yeeles J.T.P.; RT "Fast and efficient DNA replication with purified human proteins."; RL Nature 606:204-210(2022). RN [28] RP INVOLVEMENT IN FASPS4, VARIANT FASPS4 1081-ARG--ASP-1208 DEL, RP CHARACTERIZATION OF VARIANT FASPS4 1081-ARG--ASP-1208 DEL, FUNCTION, RP INTERACTION WITH CRY2 AND PER2, SUBCELLULAR LOCATION, AND DOMAIN. RX PubMed=31138685; DOI=10.1073/pnas.1819110116; RA Kurien P., Hsu P.K., Leon J., Wu D., McMahon T., Shi G., Xu Y., Lipzen A., RA Pennacchio L.A., Jones C.R., Fu Y.H., Ptacek L.J.; RT "TIMELESS mutation alters phase responsiveness and causes advanced sleep RT phase."; RL Proc. Natl. Acad. Sci. U.S.A. 116:12045-12053(2019). RN [29] {ECO:0007744|PDB:4XHT, ECO:0007744|PDB:4XHU, ECO:0007744|PDB:4XHW} RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 1000-1098 IN COMPLEX WITH PARP1, RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PARP1, AND MUTAGENESIS OF RP ARG-1081. RX PubMed=26344098; DOI=10.1016/j.molcel.2015.07.031; RA Xie S., Mortusewicz O., Ma H.T., Herr P., Poon R.Y., Helleday T., Qian C.; RT "Timeless interacts with PARP-1 to promote homologous recombination RT repair."; RL Mol. Cell 60:163-176(2015). RN [30] {ECO:0007744|PDB:5MQI} RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 1-238 AND 331-463, SUBUNIT, AND RP INTERACTION WITH TIPIN. RX PubMed=28334766; DOI=10.1093/nar/gkx139; RA Holzer S., Degliesposti G., Kilkenny M.L., Maslen S.L., Matak-Vinkovic D., RA Skehel M., Pellegrini L.; RT "Crystal structure of the N-terminal domain of human Timeless and its RT interaction with Tipin."; RL Nucleic Acids Res. 45:5555-5563(2017). RN [31] {ECO:0007744|PDB:6T9Q, ECO:0007744|PDB:6TAZ} RP X-RAY CRYSTALLOGRAPHY (1.15 ANGSTROMS) OF 883-947, STRUCTURE BY NMR OF RP 816-954, FUNCTION, AND INTERACTION WITH TIPIN AND DDX11. RX PubMed=32705708; DOI=10.15252/embj.2019104185; RA Lerner L.K., Holzer S., Kilkenny M.L., Svikovic S., Murat P., Schiavone D., RA Eldridge C.B., Bittleston A., Maman J.D., Branzei D., Stott K., RA Pellegrini L., Sale J.E.; RT "Timeless couples G-quadruplex detection with processing by DDX11 helicase RT during DNA replication."; RL EMBO J. 39:e104185-e104185(2020). RN [32] {ECO:0007744|PDB:7PFO} RP STRUCTURE BY ELECTRON MICROSCOPY (3.20 ANGSTROMS) IN REPLISOME, SUBUNIT, RP AND FUNCTION. RX PubMed=34694004; DOI=10.15252/embj.2021108819; RA Jones M.L., Baris Y., Taylor M.R.G., Yeeles J.T.P.; RT "Structure of a human replisome shows the organisation and interactions of RT a DNA replication machine."; RL EMBO J. 40:e108819-e108819(2021). RN [33] {ECO:0007744|PDB:7PLO} RP STRUCTURE BY ELECTRON MICROSCOPY (2.80 ANGSTROMS) IN REPLISOME, AND RP SUBUNIT. RX PubMed=34700328; DOI=10.1038/s41586-021-04145-3; RA Jenkyn-Bedford M., Jones M.L., Baris Y., Labib K.P.M., Cannone G., RA Yeeles J.T.P., Deegan T.D.; RT "A conserved mechanism for regulating replisome disassembly in RT eukaryotes."; RL Nature 600:743-747(2021). RN [34] RP VARIANTS [LARGE SCALE ANALYSIS] ASP-429 AND GLU-1008. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). CC -!- FUNCTION: Plays an important role in the control of DNA replication, CC maintenance of replication fork stability, maintenance of genome CC stability throughout normal DNA replication, DNA repair and in the CC regulation of the circadian clock (PubMed:9856465, PubMed:17141802, CC PubMed:17296725, PubMed:23418588, PubMed:26344098, PubMed:23359676, CC PubMed:35585232, PubMed:31138685, PubMed:32705708). Required to CC stabilize replication forks during DNA replication by forming a complex CC with TIPIN: this complex regulates DNA replication processes under both CC normal and stress conditions, stabilizes replication forks and CC influences both CHEK1 phosphorylation and the intra-S phase checkpoint CC in response to genotoxic stress (PubMed:17141802, PubMed:17296725, CC PubMed:23359676, PubMed:35585232). During DNA replication, inhibits the CC CMG complex ATPase activity and activates DNA polymerases catalytic CC activities, coupling DNA unwinding and DNA synthesis (PubMed:23359676). CC TIMELESS promotes TIPIN nuclear localization (PubMed:17141802, CC PubMed:17296725). Plays a role in maintaining processive DNA CC replication past genomic guanine-rich DNA sequences that form G- CC quadruplex (G4) structures, possibly together with DDX1 CC (PubMed:32705708). Involved in cell survival after DNA damage or CC replication stress by promoting DNA repair (PubMed:17141802, CC PubMed:17296725, PubMed:26344098, PubMed:30356214). In response to CC double-strand breaks (DSBs), accumulates at DNA damage sites and CC promotes homologous recombination repair via its interaction with PARP1 CC (PubMed:26344098, PubMed:30356214, PubMed:31138685). May be CC specifically required for the ATR-CHEK1 pathway in the replication CC checkpoint induced by hydroxyurea or ultraviolet light CC (PubMed:15798197). Involved in the determination of period length and CC in the DNA damage-dependent phase advancing of the circadian clock CC (PubMed:23418588, PubMed:31138685). Negatively regulates CLOCK|NPAS2- CC ARTNL/BMAL1|ARTNL2/BMAL2-induced transactivation of PER1 possibly via CC translocation of PER1 into the nucleus (PubMed:9856465, CC PubMed:31138685). May play a role as destabilizer of the PER2-CRY2 CC complex (PubMed:31138685). May also play an important role in CC epithelial cell morphogenesis and formation of branching tubules (By CC similarity). {ECO:0000250|UniProtKB:Q9R1X4, CC ECO:0000269|PubMed:15798197, ECO:0000269|PubMed:17141802, CC ECO:0000269|PubMed:17296725, ECO:0000269|PubMed:23359676, CC ECO:0000269|PubMed:23418588, ECO:0000269|PubMed:26344098, CC ECO:0000269|PubMed:30356214, ECO:0000269|PubMed:31138685, CC ECO:0000269|PubMed:32705708, ECO:0000269|PubMed:35585232, CC ECO:0000269|PubMed:9856465}. CC -!- SUBUNIT: Monomer (PubMed:28334766). Homodimer or homomultimer (By CC similarity). Component of the circadian core oscillator, which includes CC the CRY proteins, CLOCK or NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2, CSKN1D CC and/or CSNK1E, TIMELESS, and the PER proteins (PubMed:9856465). CC Interacts with PER2 (PubMed:31138685). The interaction with PER2 is CC direct and via its second PAS domain (By similarity). Interacts CC directly with PER1 and PER3 (By similarity). Interacts with CRY2, CC CHEK1, ATR and ATRIP (PubMed:15798197, PubMed:31138685). Interacts with CC CRY1 (By similarity) (PubMed:15798197). Interacts with CLSPN; the CC interaction is required for leading-strand replication CC (PubMed:23359676, PubMed:17141802, PubMed:35585232, PubMed:34694004, CC PubMed:34700328). Interacts (via N-terminus) with TIPIN CC (PubMed:17102137, PubMed:17116885, PubMed:17296725, PubMed:34694004, CC PubMed:34700328, PubMed:28334766). The TIMELESS-TIPIN heterodimer binds CC preferably to guanine-rich quadruplex-forming (G4) DNA structures CC (PubMed:32705708). Associates with the MCM2-7 complex (PubMed:34700328, CC PubMed:34694004, PubMed:23359676). Interacts with DNA polymerases CC alpha, delta and epsilon (PubMed:23359676). Interacts with DDX11; this CC interaction increases recruitment of both proteins onto chromatin in CC response to replication stress induction by hydroxyurea CC (PubMed:20124417, PubMed:26503245, PubMed:32705708). Interacts with CC PARP1; interaction is direct and independent of poly-ADP-ribose CC (PubMed:26344098, PubMed:30356214). {ECO:0000250|UniProtKB:Q9R1X4, CC ECO:0000269|PubMed:15798197, ECO:0000269|PubMed:17102137, CC ECO:0000269|PubMed:17116885, ECO:0000269|PubMed:17141802, CC ECO:0000269|PubMed:17296725, ECO:0000269|PubMed:20124417, CC ECO:0000269|PubMed:23359676, ECO:0000269|PubMed:26344098, CC ECO:0000269|PubMed:26503245, ECO:0000269|PubMed:28334766, CC ECO:0000269|PubMed:30356214, ECO:0000269|PubMed:31138685, CC ECO:0000269|PubMed:32705708, ECO:0000269|PubMed:34694004, CC ECO:0000269|PubMed:34700328, ECO:0000269|PubMed:35585232, CC ECO:0000269|PubMed:9856465}. CC -!- INTERACTION: CC Q9UNS1; O14757: CHEK1; NbExp=2; IntAct=EBI-2212315, EBI-974488; CC Q9UNS1; Q9BVW5: TIPIN; NbExp=2; IntAct=EBI-2212315, EBI-2515360; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:17141802, CC ECO:0000269|PubMed:31138685}. Chromosome {ECO:0000269|PubMed:26344098}. CC Note=In response to double-strand breaks (DSBs), accumulates at DNA CC damage sites via its interaction with PARP1. CC {ECO:0000269|PubMed:26344098}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1 {ECO:0000269|PubMed:9856465, ECO:0000269|PubMed:9891984}; CC IsoId=Q9UNS1-1; Sequence=Displayed; CC Name=2 {ECO:0000269|PubMed:9856465}; CC IsoId=Q9UNS1-2; Sequence=VSP_051693; CC -!- TISSUE SPECIFICITY: Expressed in all tissues examined including brain, CC heart, lung, liver, skeletal muscle, kidney, placenta, pancreas, CC spleen, thymus and testis. Highest levels of expression in placenta, CC pancreas, thymus and testis. {ECO:0000269|PubMed:9856465, CC ECO:0000269|PubMed:9891984}. CC -!- INDUCTION: Regulated by the cell cycle. High levels in S, G(2) and M CC phases, with highest level in S phase. Low expression in G(0) and G(1) CC phases. {ECO:0000269|PubMed:15798197}. CC -!- DOMAIN: Residues 1182-1199 comprise a putative nuclear localization CC signal; nuclear localization is required for the regulation of period CC length of the circadian clock. {ECO:0000269|PubMed:31138685}. CC -!- DOMAIN: The DNA-binding domain (residues 816-954) binds to both single- CC stranded DNA (ssDNA) and double-stranded DNA (dsDNA), and has high CC affinity for DNA sequences rich in guanine that form G-quadruplex (G4) CC structures. {ECO:0000269|PubMed:32705708}. CC -!- DOMAIN: The C-terminal domain, comprising the DNA-binding domain and CC the PARP1-binding region, is required for the replication past genomic CC guanine-rich DNA sequences that form G-quadruplex (G4) structures. CC {ECO:0000269|PubMed:32705708}. CC -!- DISEASE: Advanced sleep phase syndrome, familial, 4 (FASPS4) CC [MIM:620015]: An autosomal dominant disorder characterized by very CC early sleep onset and offset. Individuals are 'morning larks' with a 4 CC hours advance of the sleep, temperature and melatonin rhythms. CC {ECO:0000269|PubMed:31138685}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the timeless family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH39842.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/timeless/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB015597; BAA36499.1; -; mRNA. DR EMBL; AF098162; AAC80011.1; -; mRNA. DR EMBL; EU627094; ACD11488.1; -; Genomic_DNA. DR EMBL; AC024884; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC039842; AAH39842.1; ALT_SEQ; mRNA. DR EMBL; BC050557; AAH50557.1; -; mRNA. DR CCDS; CCDS81699.1; -. [Q9UNS1-2] DR CCDS; CCDS8918.1; -. [Q9UNS1-1] DR RefSeq; NP_001317224.1; NM_001330295.1. [Q9UNS1-2] DR RefSeq; NP_003911.2; NM_003920.4. [Q9UNS1-1] DR PDB; 4XHT; X-ray; 1.65 A; A/B/C/D=1000-1098. DR PDB; 4XHU; X-ray; 2.09 A; B/D=1000-1098. DR PDB; 4XHW; X-ray; 2.85 A; A/B/C/D=1000-1098. DR PDB; 5MQI; X-ray; 1.85 A; A=1-238, A=331-463. DR PDB; 6T9Q; X-ray; 1.15 A; A=883-947. DR PDB; 6TAZ; NMR; -; B=816-954. DR PDB; 7PFO; EM; 3.20 A; K=1-1208. DR PDB; 7PLO; EM; 2.80 A; K=1-1208. DR PDB; 8B9D; EM; 3.40 A; K=1-1208. DR PDBsum; 4XHT; -. DR PDBsum; 4XHU; -. DR PDBsum; 4XHW; -. DR PDBsum; 5MQI; -. DR PDBsum; 6T9Q; -. DR PDBsum; 6TAZ; -. DR PDBsum; 7PFO; -. DR PDBsum; 7PLO; -. DR PDBsum; 8B9D; -. DR AlphaFoldDB; Q9UNS1; -. DR EMDB; EMD-13375; -. DR EMDB; EMD-13494; -. DR SMR; Q9UNS1; -. DR BioGRID; 114428; 133. DR ComplexPortal; CPX-2526; Replication fork protection complex. DR DIP; DIP-47395N; -. DR IntAct; Q9UNS1; 31. DR MINT; Q9UNS1; -. DR STRING; 9606.ENSP00000450607; -. DR iPTMnet; Q9UNS1; -. DR PhosphoSitePlus; Q9UNS1; -. DR BioMuta; TIMELESS; -. DR DMDM; 296452931; -. DR EPD; Q9UNS1; -. DR jPOST; Q9UNS1; -. DR MassIVE; Q9UNS1; -. DR MaxQB; Q9UNS1; -. DR PaxDb; 9606-ENSP00000450607; -. DR PeptideAtlas; Q9UNS1; -. DR ProteomicsDB; 85326; -. [Q9UNS1-1] DR ProteomicsDB; 85327; -. [Q9UNS1-2] DR Pumba; Q9UNS1; -. DR Antibodypedia; 15850; 256 antibodies from 31 providers. DR DNASU; 8914; -. DR Ensembl; ENST00000229201.4; ENSP00000229201.4; ENSG00000111602.12. [Q9UNS1-2] DR Ensembl; ENST00000553532.6; ENSP00000450607.1; ENSG00000111602.12. [Q9UNS1-1] DR GeneID; 8914; -. DR KEGG; hsa:8914; -. DR MANE-Select; ENST00000553532.6; ENSP00000450607.1; NM_003920.5; NP_003911.2. DR UCSC; uc001slf.3; human. [Q9UNS1-1] DR AGR; HGNC:11813; -. DR CTD; 8914; -. DR DisGeNET; 8914; -. DR GeneCards; TIMELESS; -. DR HGNC; HGNC:11813; TIMELESS. DR HPA; ENSG00000111602; Low tissue specificity. DR MalaCards; TIMELESS; -. DR MIM; 603887; gene. DR MIM; 620015; phenotype. DR neXtProt; NX_Q9UNS1; -. DR OpenTargets; ENSG00000111602; -. DR PharmGKB; PA36520; -. DR VEuPathDB; HostDB:ENSG00000111602; -. DR eggNOG; KOG1974; Eukaryota. DR GeneTree; ENSGT00390000015124; -. DR HOGENOM; CLU_003493_0_0_1; -. DR InParanoid; Q9UNS1; -. DR OMA; KETHDYK; -. DR OrthoDB; 2877878at2759; -. DR PhylomeDB; Q9UNS1; -. DR TreeFam; TF312802; -. DR PathwayCommons; Q9UNS1; -. DR Reactome; R-HSA-5693607; Processing of DNA double-strand break ends. DR SignaLink; Q9UNS1; -. DR SIGNOR; Q9UNS1; -. DR BioGRID-ORCS; 8914; 760 hits in 1140 CRISPR screens. DR ChiTaRS; TIMELESS; human. DR GenomeRNAi; 8914; -. DR Pharos; Q9UNS1; Tbio. DR PRO; PR:Q9UNS1; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q9UNS1; Protein. DR Bgee; ENSG00000111602; Expressed in ventricular zone and 136 other cell types or tissues. DR GO; GO:0000785; C:chromatin; IDA:HGNC-UCL. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:HGNC-UCL. DR GO; GO:0031298; C:replication fork protection complex; IBA:GO_Central. DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB. DR GO; GO:0003677; F:DNA binding; IBA:GO_Central. DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl. DR GO; GO:0048754; P:branching morphogenesis of an epithelial tube; IEA:Ensembl. DR GO; GO:0044770; P:cell cycle phase transition; IMP:BHF-UCL. DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW. DR GO; GO:1904976; P:cellular response to bleomycin; IMP:UniProtKB. DR GO; GO:0072719; P:cellular response to cisplatin; IMP:UniProtKB. DR GO; GO:0072711; P:cellular response to hydroxyurea; IMP:UniProtKB. DR GO; GO:0007623; P:circadian rhythm; ISS:UniProtKB. DR GO; GO:0009582; P:detection of abiotic stimulus; TAS:ProtInc. DR GO; GO:0006974; P:DNA damage response; IMP:UniProtKB. DR GO; GO:0006281; P:DNA repair; IBA:GO_Central. DR GO; GO:0000076; P:DNA replication checkpoint signaling; IBA:GO_Central. DR GO; GO:0030324; P:lung development; IEA:Ensembl. DR GO; GO:0002009; P:morphogenesis of an epithelium; ISS:UniProtKB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:2000781; P:positive regulation of double-strand break repair; IMP:UniProtKB. DR GO; GO:1905168; P:positive regulation of double-strand break repair via homologous recombination; IDA:UniProtKB. DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:UniProtKB. DR GO; GO:0043111; P:replication fork arrest; IBA:GO_Central. DR InterPro; IPR044998; Timeless. DR InterPro; IPR007725; TIMELESS_C. DR InterPro; IPR006906; Timeless_N. DR PANTHER; PTHR22940:SF4; PROTEIN TIMELESS HOMOLOG; 1. DR PANTHER; PTHR22940; TIMEOUT/TIMELESS-2; 1. DR Pfam; PF04821; TIMELESS; 1. DR Pfam; PF05029; TIMELESS_C; 1. DR Genevisible; Q9UNS1; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Biological rhythms; Cell cycle; KW Cell division; Chromosome; Developmental protein; Disease variant; KW DNA damage; DNA repair; Mitosis; Nucleus; Phosphoprotein; KW Reference proteome; Transcription; Transcription regulation. FT CHAIN 1..1208 FT /note="Protein timeless homolog" FT /id="PRO_0000072538" FT REGION 1..309 FT /note="Required for homodimerization and for interaction FT with CRY1 and CHEK1" FT /evidence="ECO:0000250|UniProtKB:Q9R1X4" FT REGION 655..679 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 816..954 FT /note="DNA-binding domain" FT /evidence="ECO:0000269|PubMed:32705708" FT REGION 971..994 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1000..1098 FT /note="Interaction with PARP1" FT /evidence="ECO:0000269|PubMed:26344098" FT REGION 1091..1131 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1143..1208 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1182..1199 FT /note="Required for nuclear localization" FT /evidence="ECO:0000269|PubMed:31138685" FT COMPBIAS 664..679 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 971..991 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1092..1106 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1117..1131 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1145..1173 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 281 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1074 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1087 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1089 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1149 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1173 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:16964243, FT ECO:0007744|PubMed:17081983, ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT VAR_SEQ 177 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:9856465" FT /id="VSP_051693" FT VARIANT 129 FT /note="A -> S (in dbSNP:rs72478986)" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_047879" FT VARIANT 429 FT /note="A -> D (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036435" FT VARIANT 455 FT /note="I -> L (in dbSNP:rs774027)" FT /evidence="ECO:0000269|PubMed:9856465, FT ECO:0000269|PubMed:9891984, ECO:0000269|Ref.3" FT /id="VAR_021483" FT VARIANT 471 FT /note="N -> S (in dbSNP:rs72478993)" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_047880" FT VARIANT 831 FT /note="R -> Q (in dbSNP:rs774047)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:9856465, ECO:0000269|Ref.3" FT /id="VAR_021484" FT VARIANT 870 FT /note="M -> V (in dbSNP:rs61733875)" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_047881" FT VARIANT 922 FT /note="R -> H (in dbSNP:rs72478999)" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_047882" FT VARIANT 924 FT /note="R -> W (in dbSNP:rs72479000)" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_047883" FT VARIANT 1008 FT /note="Q -> E (in a breast cancer sample; somatic mutation; FT dbSNP:rs151188513)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036436" FT VARIANT 1017 FT /note="I -> T (in dbSNP:rs61376834)" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_047884" FT VARIANT 1018 FT /note="P -> L (in dbSNP:rs2291739)" FT /evidence="ECO:0000269|PubMed:15489334, ECO:0000269|Ref.3" FT /id="VAR_021485" FT VARIANT 1081..1208 FT /note="Missing (in FASPS4; reduced protein stability; FT mislocalization in cytoplasm; reduced interaction with FT CRY2; enhanced destabilization of the PER2-CRY2 complex; FT reduced repressor activity of FT CLOCK|NPAS2-ARTNL/BMAL1|ARTNL2/BMAL2-induced FT transactivation of PER1; does not affect interaction with FT PER2; dbSNP:rs1465092391)" FT /evidence="ECO:0000269|PubMed:31138685" FT /id="VAR_087625" FT MUTAGEN 1081 FT /note="R->G: Abolishes interaction with PARP1." FT /evidence="ECO:0000269|PubMed:26344098" FT HELIX 8..15 FT /evidence="ECO:0007829|PDB:5MQI" FT STRAND 17..21 FT /evidence="ECO:0007829|PDB:5MQI" FT STRAND 24..27 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 31..43 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 50..58 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 60..63 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 65..71 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 76..89 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 93..97 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 106..123 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 127..142 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 145..147 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 150..168 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 184..195 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 198..207 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 209..214 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 215..225 FT /evidence="ECO:0007829|PDB:5MQI" FT TURN 226..228 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 231..234 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 336..352 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 354..367 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 369..371 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 376..391 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 396..402 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 405..424 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 426..428 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 429..451 FT /evidence="ECO:0007829|PDB:5MQI" FT HELIX 824..837 FT /evidence="ECO:0007829|PDB:6TAZ" FT STRAND 838..843 FT /evidence="ECO:0007829|PDB:6TAZ" FT HELIX 845..852 FT /evidence="ECO:0007829|PDB:6TAZ" FT HELIX 860..869 FT /evidence="ECO:0007829|PDB:6TAZ" FT HELIX 876..880 FT /evidence="ECO:0007829|PDB:6TAZ" FT HELIX 891..904 FT /evidence="ECO:0007829|PDB:6T9Q" FT HELIX 910..916 FT /evidence="ECO:0007829|PDB:6T9Q" FT HELIX 924..933 FT /evidence="ECO:0007829|PDB:6T9Q" FT STRAND 936..939 FT /evidence="ECO:0007829|PDB:6T9Q" FT HELIX 940..943 FT /evidence="ECO:0007829|PDB:6T9Q" FT HELIX 1008..1012 FT /evidence="ECO:0007829|PDB:4XHT" FT HELIX 1016..1033 FT /evidence="ECO:0007829|PDB:4XHT" FT STRAND 1042..1044 FT /evidence="ECO:0007829|PDB:4XHW" FT HELIX 1049..1055 FT /evidence="ECO:0007829|PDB:4XHT" FT HELIX 1058..1067 FT /evidence="ECO:0007829|PDB:4XHT" FT TURN 1074..1076 FT /evidence="ECO:0007829|PDB:4XHT" FT STRAND 1078..1082 FT /evidence="ECO:0007829|PDB:4XHW" FT HELIX 1088..1096 FT /evidence="ECO:0007829|PDB:4XHT" SQ SEQUENCE 1208 AA; 138658 MW; 16C6C07DDC6D2701 CRC64; MDLHMMNCEL LATCSALGYL EGDTYHKEPD CLESVKDLIR YLRHEDETRD VRQQLGAAQI LQSDLLPILT QHHQDKPLFD AVIRLMVNLT QPALLCFGNL PKEPSFRHHF LQVLTYLQAY KEAFASEKAF GVLSETLYEL LQLGWEERQE EDNLLIERIL LLVRNILHVP ADLDQEKKID DDASAHDQLL WAIHLSGLDD LLLFLASSSA EEQWSLHVLE IVSLMFRDQN PEQLAGVGQG RLAQERSADF AELEVLRQRE MAEKKTRALQ RGNRHSRFGG SYIVQGLKSI GERDLIFHKG LHNLRNYSSD LGKQPKKVPK RRQAARELSI QRRSALNVRL FLRDFCSEFL ENCYNRLMGS VKDHLLREKA QQHDETYYMW ALAFFMAFNR AASFRPGLVS ETLSVRTFHF IEQNLTNYYE MMLTDRKEAA SWARRMHLAL KAYQELLATV NEMDISPDEA VRESSRIIKN NIFYVMEYRE LFLALFRKFD ERCQPRSFLR DLVETTHLFL KMLERFCRSR GNLVVQNKQK KRRKKKKKVL DQAIVSGNVP SSPEEVEAVW PALAEQLQCC AQNSELSMDS VVPFDAASEV PVEEQRAEAM VRIQDCLLAG QAPQALTLLR SAREVWPEGD VFGSQDISPE EEIQLLKQIL SAPLPRQQGP EERGAEEEEE EEEEEEEELQ VVQVSEKEFN FLDYLKRFAC STVVRAYVLL LRSYQQNSAH TNHCIVKMLH RLAHDLKMEA LLFQLSVFCL FNRLLSDPAA GAYKELVTFA KYILGKFFAL AAVNQKAFVE LLFWKNTAVV REMTEGYGSL DDRSSSRRAP TWSPEEEAHL RELYLANKDV EGQDVVEAIL AHLNTVPRTR KQIIHHLVQM GLADSVKDFQ RKGTHIVLWT GDQELELQRL FEEFRDSDDV LGHIMKNITA KRSRARIVDK LLALGLVAER RELYKKRQKK LASSILPNGA ESLKDFCQED LEEEENLPEE DSEEEEEGGS EAEQVQGSLV LSNENLGQSL HQEGFSIPLL WLQNCLIRAA DDREEDGCSQ AVPLVPLTEE NEEAMENEQF QQLLRKLGVR PPASGQETFW RIPAKLSPTQ LRRAAASLSQ PEEEQKLQPE LQPKVPGEQG SDEEHCKEHR AQALRALLLA HKKKAGLASP EEEDAVGKEP LKAAPKKRQL LDSDEEQEED EGRNRAPELG APGIQKKKRY QIEDDEDD //