ID CLOCK_HUMAN Reviewed; 846 AA. AC O15516; A0AV01; A2I2N9; O14516; Q9UIT8; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 1. DT 27-MAR-2024, entry version 222. DE RecName: Full=Circadian locomoter output cycles protein kaput; DE Short=hCLOCK; DE EC=2.3.1.48; DE AltName: Full=Class E basic helix-loop-helix protein 8; DE Short=bHLHe8; GN Name=CLOCK; Synonyms=BHLHE8, KIAA0334; 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 [GENOMIC DNA / MRNA], AND TISSUE SPECIFICITY. RX PubMed=10198158; DOI=10.1006/geno.1998.5675; RA Steeves T.D.L., King D.P., Zhao Y., Sangoram A.M., Du F., Bowcock A.M., RA Moore R.Y., Takahashi J.S.; RT "Molecular cloning and characterization of the human CLOCK gene: expression RT in the suprachiasmatic nuclei."; RL Genomics 57:189-200(1999). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NHLBI resequencing and genotyping service (RS&G); RL Submitted (SEP-2006) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=9205841; DOI=10.1093/dnares/4.2.141; RA Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., Miyajima N., RA Tanaka A., Kotani H., Nomura N., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. VII. The RT complete sequences of 100 new cDNA clones from brain which can code for RT large proteins in vitro."; RL DNA Res. 4:141-150(1997). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Placenta; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lung; 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 NUCLEOTIDE SEQUENCE [MRNA] OF 1-349. RC TISSUE=Brain; RA Ikeda M., Takehara N., Ebisawa T., Yamauchi T., Nomura M.; RT "Molecular cloning of human Clock cDNA 5'-end."; RL Submitted (AUG-1997) to the EMBL/GenBank/DDBJ databases. RN [7] RP DNA-BINDING, AND ACTIVITY REGULATION. RX PubMed=11441146; DOI=10.1126/science.1060698; RA Rutter J., Reick M., Wu L.C., McKnight S.L.; RT "Regulation of clock and NPAS2 DNA binding by the redox state of NAD RT cofactors."; RL Science 293:510-514(2001). RN [8] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH KAT2B; CREBBP AND RP EP300. RX PubMed=14645221; DOI=10.1074/jbc.m311973200; RA Curtis A.M., Seo S.B., Westgate E.J., Rudic R.D., Smyth E.M., RA Chakravarti D., FitzGerald G.A., McNamara P.; RT "Histone acetyltransferase-dependent chromatin remodeling and the vascular RT clock."; RL J. Biol. Chem. 279:7091-7097(2004). RN [9] RP MUTAGENESIS OF GLU-116; GLY-332; HIS-360; GLU-367; VAL-601 AND PRO-840. RX PubMed=16474406; DOI=10.1038/ng1745; RA Sato T.K., Yamada R.G., Ukai H., Baggs J.E., Miraglia L.J., Kobayashi T.J., RA Welsh D.K., Kay S.A., Ueda H.R., Hogenesch J.B.; RT "Feedback repression is required for mammalian circadian clock function."; RL Nat. Genet. 38:312-319(2006). RN [10] RP FUNCTION. RX PubMed=18587630; DOI=10.1007/s11010-008-9846-x; RA Li R., Yue J., Zhang Y., Zhou L., Hao W., Yuan J., Qiang B., Ding J.M., RA Peng X., Cao J.M.; RT "CLOCK/BMAL1 regulates human nocturnin transcription through binding to the RT E-box of nocturnin promoter."; RL Mol. Cell. Biochem. 317:169-177(2008). RN [11] RP INTERACTION WITH ID2. RX PubMed=20861012; DOI=10.1074/jbc.m110.175182; RA Ward S.M., Fernando S.J., Hou T.Y., Duffield G.E.; RT "The transcriptional repressor ID2 can interact with the canonical clock RT components CLOCK and BMAL1 and mediate inhibitory effects on mPer1 RT expression."; RL J. Biol. Chem. 285:38987-39000(2010). RN [12] RP INTERACTION WITH BMAL1; CRY1 AND PER2. RX PubMed=21613214; DOI=10.1074/jbc.m111.254680; RA Ye R., Selby C.P., Ozturk N., Annayev Y., Sancar A.; RT "Biochemical analysis of the canonical model for the mammalian circadian RT clock."; RL J. Biol. Chem. 286:25891-25902(2011). RN [13] RP FUNCTION, AND INTERACTION WITH NR3C1. RX PubMed=21980503; DOI=10.1371/journal.pone.0025612; RA Charmandari E., Chrousos G.P., Lambrou G.I., Pavlaki A., Koide H., Ng S.S., RA Kino T.; RT "Peripheral CLOCK regulates target-tissue glucocorticoid receptor RT transcriptional activity in a circadian fashion in man."; RL PLoS ONE 6:E25612-E25612(2011). RN [14] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=21659603; DOI=10.1126/science.1203430; RA Cotta-Ramusino C., McDonald E.R. III, Hurov K., Sowa M.E., Harper J.W., RA Elledge S.J.; RT "A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 RT interacting protein required for ATR signaling."; RL Science 332:1313-1317(2011). RN [15] RP INTERACTION WITH KDM5A. RX PubMed=21960634; DOI=10.1126/science.1206022; RA DiTacchio L., Le H.D., Vollmers C., Hatori M., Witcher M., Secombe J., RA Panda S.; RT "Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences RT the circadian clock."; RL Science 333:1881-1885(2011). RN [16] RP FUNCTION. RX PubMed=22284746; DOI=10.1111/j.1538-7836.2012.04643.x; RA Tracey C.J., Pan X., Catterson J.H., Harmar A.J., Hussain M.M., RA Hartley P.S.; RT "Diurnal expression of the thrombopoietin gene is regulated by CLOCK."; RL J. Thromb. Haemost. 10:662-669(2012). RN [17] RP REVIEW. RX PubMed=23576606; DOI=10.1152/ajpregu.00066.2013; RA Richards J., Gumz M.L.; RT "Mechanism of the circadian clock in physiology."; RL Am. J. Physiol. 304:R1053-R1064(2013). RN [18] RP PHOSPHORYLATION AT THR-451 AND THR-461, MUTAGENESIS OF THR-451 AND THR-461, RP AND INTERACTION WITH THE COMPLEX P35/CDK5. RX PubMed=24235147; DOI=10.1074/jbc.m113.494856; RA Kwak Y., Jeong J., Lee S., Park Y.U., Lee S.A., Han D.H., Kim J.H., RA Ohshima T., Mikoshiba K., Suh Y.H., Cho S., Park S.K.; RT "Cyclin-dependent kinase 5 (Cdk5) regulates the function of CLOCK protein RT by direct phosphorylation."; RL J. Biol. Chem. 288:36878-36889(2013). RN [19] RP FUNCTION. RX PubMed=23785138; DOI=10.1523/jneurosci.2757-12.2013; RA Baeza-Raja B., Eckel-Mahan K., Zhang L., Vagena E., Tsigelny I.F., RA Sassone-Corsi P., Ptacek L.J., Akassoglou K.; RT "p75 neurotrophin receptor is a clock gene that regulates oscillatory RT components of circadian and metabolic networks."; RL J. Neurosci. 33:10221-10234(2013). RN [20] RP SUMOYLATION, SUBCELLULAR LOCATION, AND INTERACTION WITH ESR1. RX PubMed=23160374; DOI=10.1038/onc.2012.518; RA Li S., Wang M., Ao X., Chang A.K., Yang C., Zhao F., Bi H., Liu Y., RA Xiao L., Wu H.; RT "CLOCK is a substrate of SUMO and sumoylation of CLOCK upregulates the RT transcriptional activity of estrogen receptor-alpha."; RL Oncogene 32:4883-4891(2013). RN [21] RP REVIEW. RX PubMed=23303907; DOI=10.1152/physrev.00016.2012; RA Eckel-Mahan K., Sassone-Corsi P.; RT "Metabolism and the circadian clock converge."; RL Physiol. Rev. 93:107-135(2013). RN [22] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=24005054; DOI=10.1038/jid.2013.366; RA Al-Nuaimi Y., Hardman J.A., Biro T., Haslam I.S., Philpott M.P., Toth B.I., RA Farjo N., Farjo B., Baier G., Watson R.E., Grimaldi B., Kloepper J.E., RA Paus R.; RT "A meeting of two chronobiological systems: circadian proteins Period1 and RT BMAL1 modulate the human hair cycle clock."; RL J. Invest. Dermatol. 134:610-619(2014). RN [23] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [24] RP REVIEW. RX PubMed=23916625; DOI=10.1016/j.tcb.2013.07.002; RA Partch C.L., Green C.B., Takahashi J.S.; RT "Molecular architecture of the mammalian circadian clock."; RL Trends Cell Biol. 24:90-99(2014). RN [25] RP ASSOCIATION WITH PASD1. RX PubMed=25936801; DOI=10.1016/j.molcel.2015.03.031; RA Michael A.K., Harvey S.L., Sammons P.J., Anderson A.P., Kopalle H.M., RA Banham A.H., Partch C.L.; RT "Cancer/testis antigen PASD1 silences the circadian clock."; RL Mol. Cell 58:743-754(2015). RN [26] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH BMAL1; ASS1; NDUFA9 RP AND IMPDH2. RX PubMed=28985504; DOI=10.1016/j.molcel.2017.09.008; RA Lin R., Mo Y., Zha H., Qu Z., Xie P., Zhu Z.J., Xu Y., Xiong Y., Guan K.L.; RT "CLOCK acetylates ASS1 to drive circadian rhythm of ureagenesis."; RL Mol. Cell 68:198-209(2017). RN [27] RP INTERACTION WITH PIWIL2. RX PubMed=28903391; DOI=10.18632/oncotarget.18973; RA Lu Y., Zheng X., Hu W., Bian S., Zhang Z., Tao D., Liu Y., Ma Y.; RT "Cancer/testis antigen PIWIL2 suppresses circadian rhythms by regulating RT the stability and activity of BMAL1 and CLOCK."; RL Oncotarget 8:54913-54924(2017). RN [28] RP INTERACTION WITH HNF4A. RX PubMed=30530698; DOI=10.1073/pnas.1816411115; RA Qu M., Duffy T., Hirota T., Kay S.A.; RT "Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue- RT specific circadian networks."; RL Proc. Natl. Acad. Sci. U.S.A. 115:E12305-E12312(2018). RN [29] RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 29-89 IN COMPLEX WITH BMAL1 AND RP DNA, FUNCTION, ACTIVITY REGULATION, SUBUNIT, AND MUTAGENESIS OF SER-38; RP SER-42; PHE-50 AND HIS-84. RX PubMed=23229515; DOI=10.1038/cr.2012.170; RA Wang Z., Wu Y., Li L., Su X.D.; RT "Intermolecular recognition revealed by the complex structure of human RT CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA."; RL Cell Res. 23:213-224(2013). CC -!- FUNCTION: Transcriptional activator which forms a core component of the CC circadian clock. The circadian clock, an internal time-keeping system, CC regulates various physiological processes through the generation of CC approximately 24 hour circadian rhythms in gene expression, which are CC translated into rhythms in metabolism and behavior. It is derived from CC the Latin roots 'circa' (about) and 'diem' (day) and acts as an CC important regulator of a wide array of physiological functions CC including metabolism, sleep, body temperature, blood pressure, CC endocrine, immune, cardiovascular, and renal function. Consists of two CC major components: the central clock, residing in the suprachiasmatic CC nucleus (SCN) of the brain, and the peripheral clocks that are present CC in nearly every tissue and organ system. Both the central and CC peripheral clocks can be reset by environmental cues, also known as CC Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the CC central clock is light, which is sensed by retina and signals directly CC to the SCN. The central clock entrains the peripheral clocks through CC neuronal and hormonal signals, body temperature and feeding-related CC cues, aligning all clocks with the external light/dark cycle. Circadian CC rhythms allow an organism to achieve temporal homeostasis with its CC environment at the molecular level by regulating gene expression to CC create a peak of protein expression once every 24 hours to control when CC a particular physiological process is most active with respect to the CC solar day. Transcription and translation of core clock components CC (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a CC critical role in rhythm generation, whereas delays imposed by post- CC translational modifications (PTMs) are important for determining the CC period (tau) of the rhythms (tau refers to the period of a rhythm and CC is the length, in time, of one complete cycle). A diurnal rhythm is CC synchronized with the day/night cycle, while the ultradian and CC infradian rhythms have a period shorter and longer than 24 hours, CC respectively. Disruptions in the circadian rhythms contribute to the CC pathology of cardiovascular diseases, cancer, metabolic syndromes and CC aging. A transcription/translation feedback loop (TTFL) forms the core CC of the molecular circadian clock mechanism. Transcription factors, CC CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the CC feedback loop, act in the form of a heterodimer and activate the CC transcription of core clock genes and clock-controlled genes (involved CC in key metabolic processes), harboring E-box elements (5'-CACGTG-3') CC within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which CC are transcriptional repressors form the negative limb of the feedback CC loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer CC inhibiting its activity and thereby negatively regulating their own CC expression. This heterodimer also activates nuclear receptors NR1D1/2 CC and RORA/B/G, which form a second feedback loop and which activate and CC repress BMAL1 transcription, respectively. Regulates the circadian CC expression of ICAM1, VCAM1, CCL2, THPO and MPL and also acts as an CC enhancer of the transactivation potential of NF-kappaB. Plays an CC important role in the homeostatic regulation of sleep. The CLOCK-BMAL1 CC heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, CC B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, CC NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated CC in glucose and lipid metabolism. Promotes rhythmic chromatin opening, CC regulating the DNA accessibility of other transcription factors. The CC CLOCK-BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 CC and BHLHE40/DEC1. The preferred binding motif for the CLOCK-BMAL1 CC heterodimer is 5'-CACGTGA-3', which contains a flanking adenine CC nucleotide at the 3-prime end of the canonical 6-nucleotide E-box CC sequence (PubMed:23229515). CLOCK specifically binds to the half-site CC 5'-CAC-3', while BMAL1 binds to the half-site 5'-GTGA-3' CC (PubMed:23229515). The CLOCK-BMAL1 heterodimer also recognizes the non- CC canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3' CC (PubMed:23229515). CLOCK has an intrinsic acetyltransferase activity, CC which enables circadian chromatin remodeling by acetylating histones CC and nonhistone proteins, including its own partner BMAL1. Represses CC glucocorticoid receptor NR3C1/GR-induced transcriptional activity by CC reducing the association of NR3C1/GR to glucocorticoid response CC elements (GREs) via the acetylation of multiple lysine residues located CC in its hinge region (PubMed:21980503). The acetyltransferase activity CC of CLOCK is as important as its transcription activity in circadian CC control. Acetylates metabolic enzymes IMPDH2 and NDUFA9 in a circadian CC manner. Facilitated by BMAL1, rhythmically interacts and acetylates CC argininosuccinate synthase 1 (ASS1) leading to enzymatic inhibition of CC ASS1 as well as the circadian oscillation of arginine biosynthesis and CC subsequent ureagenesis (PubMed:28985504). Drives the circadian rhythm CC of blood pressure through transcriptional activation of ATP1B1 (By CC similarity). {ECO:0000250|UniProtKB:O08785, CC ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:18587630, CC ECO:0000269|PubMed:21659603, ECO:0000269|PubMed:21980503, CC ECO:0000269|PubMed:22284746, ECO:0000269|PubMed:23229515, CC ECO:0000269|PubMed:23785138, ECO:0000269|PubMed:24005054, CC ECO:0000269|PubMed:28985504}. CC -!- CATALYTIC ACTIVITY: CC Reaction=acetyl-CoA + L-lysyl-[protein] = CoA + H(+) + N(6)-acetyl-L- CC lysyl-[protein]; Xref=Rhea:RHEA:45948, Rhea:RHEA-COMP:9752, CC Rhea:RHEA-COMP:10731, ChEBI:CHEBI:15378, ChEBI:CHEBI:29969, CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57288, ChEBI:CHEBI:61930; EC=2.3.1.48; CC -!- ACTIVITY REGULATION: There is conflicting data about the effect of NAD CC cofactors on activity. PubMed:11441146 suggests that the redox state of CC the cell can modulate the transcriptional activity of the CLOCK-BMAL1 CC heterodimer; NADH and NADPH enhance the DNA-binding activity of the CC heterodimer. PubMed:23229515 reports that NADH and NADPH have no CC significant effect on DNA-binding activity of the CLOCK-BMAL1 CC heterodimer. {ECO:0000269|PubMed:11441146, CC ECO:0000269|PubMed:23229515}. CC -!- SUBUNIT: Component of the circadian clock oscillator which includes the CC CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, CC TIMELESS and the PER proteins (By similarity). Interacts with KMT2A; in CC a circadian manner (By similarity). Forms a heterodimer with BMAL1 CC (PubMed:21613214, PubMed:23229515). The CLOCK-BMAL1 heterodimer is CC required for E-box-dependent transactivation, for CLOCK nuclear CC translocation and degradation, and for phosphorylation of both CLOCK CC and BMAL1 (By similarity). Interacts with NR3C1 in a ligand-dependent CC fashion (PubMed:21980503). Interacts with ESR1 and estrogen stimulates CC this interaction (PubMed:23160374). Interacts with the complex p35/CDK5 CC (PubMed:24235147). Interacts with RELA/p65 (By similarity). Interacts CC with KAT2B, CREBBP, EP300 (PubMed:14645221). Interacts with ID1 and ID3 CC (By similarity). Interacts with ID2 (PubMed:20861012). Interacts with CC MTA1 (By similarity). Interacts with OGA (By similarity). Interacts CC with SIRT1 (By similarity). Interacts with CIPC (By similarity). CC Interacts with EZH2 (By similarity). Interacts with EIF4E, PIWIL1 and CC DDX4 (By similarity). Interacts with PER2 and CRY1 and the interaction CC with PER and CRY proteins requires translocation to the nucleus. CC Interacts with PER1 and CRY2 (By similarity). Interaction of the CLOCK- CC BMAL1 heterodimer with PER or CRY inhibits transcription activation CC (PubMed:21613214). Interaction of the CLOCK-BMAL1 with CRY1 is CC independent of DNA but with PER2 is off DNA (PubMed:21613214). The CC CLOCK-BMAL1 heterodimer interacts with GSK3B. Interacts with KDM5A CC (PubMed:21960634). Interacts with MYBBP1A (By similarity). Interacts CC with THRAP3 (By similarity). Interacts with MED1; this interaction CC requires the presence of THRAP3 (By similarity). Interacts with NCOA2 CC (By similarity). The CLOCK-BMAL1 heterodimer interacts with PASD1 CC (PubMed:25936801). Interacts with ASS1 and IMPDH2; in a circadian CC manner (PubMed:28985504). Interacts with NDUFA9 (PubMed:28985504). CC Interacts with PIWIL2 (via PIWI domain) (PubMed:28903391). Interacts CC with HNF4A (PubMed:30530698). {ECO:0000250|UniProtKB:O08785, CC ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:20861012, CC ECO:0000269|PubMed:21613214, ECO:0000269|PubMed:21960634, CC ECO:0000269|PubMed:21980503, ECO:0000269|PubMed:23160374, CC ECO:0000269|PubMed:23229515, ECO:0000269|PubMed:24235147, CC ECO:0000269|PubMed:25936801, ECO:0000269|PubMed:28903391, CC ECO:0000269|PubMed:28985504, ECO:0000269|PubMed:30530698}. CC -!- INTERACTION: CC O15516; O00327: BMAL1; NbExp=4; IntAct=EBI-1794265, EBI-1794206; CC O15516; O00327-8: BMAL1; NbExp=6; IntAct=EBI-1794265, EBI-11991546; CC O15516; Q8WYA1-3: BMAL2; NbExp=4; IntAct=EBI-1794265, EBI-12268276; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:14645221, CC ECO:0000269|PubMed:23160374, ECO:0000269|PubMed:28985504}. Cytoplasm CC {ECO:0000250|UniProtKB:O08785}. Cytoplasm, cytosol CC {ECO:0000269|PubMed:28985504}. Note=Shuttling between the cytoplasm and CC the nucleus is under circadian regulation and is BMAL1-dependent. CC Phosphorylated form located in the nucleus while the nonphosphorylated CC form found only in the cytoplasm. Sequestered to the cytoplasm in the CC presence of ID2 (By similarity). Localizes to sites of DNA damage in a CC H2AX-independent manner. {ECO:0000250|UniProtKB:O08785, CC ECO:0000269|PubMed:21659603}. CC -!- TISSUE SPECIFICITY: Hair follicles (at protein level). Expressed in all CC tissues examined including spleen, thymus, prostate, testis, ovary, CC small intestine, colon, leukocytes, heart, brain, placenta, lung, CC liver, skeletal muscle, kidney and pancreas. Highest levels in testis CC and skeletal muscle. Low levels in thymus, lung and liver. Expressed in CC all brain regions with highest levels in cerebellum. Highly expressed CC in the suprachiasmatic nucleus (SCN). {ECO:0000269|PubMed:10198158, CC ECO:0000269|PubMed:24005054}. CC -!- PTM: Ubiquitinated, leading to its proteasomal degradation. CC {ECO:0000250|UniProtKB:O08785}. CC -!- PTM: O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents CC protein degradation by inhibiting ubiquitination. It also stabilizes CC the CLOCK-BMAL1 heterodimer thereby increasing CLOCK-BMAL1-mediated CC transcriptional activation of PER1/2/3 and CRY1/2. CC {ECO:0000250|UniProtKB:O08785}. CC -!- PTM: Phosphorylation is dependent on the CLOCK-BMAL1 heterodimer CC formation. Phosphorylation enhances the transcriptional activity, CC alters the subcellular localization and decreases the stability of the CC heterodimer by promoting its degradation. Phosphorylation shows CC circadian variations in the liver. May be phosphorylated by CSNK1D and CC CKSN1E. {ECO:0000269|PubMed:24235147}. CC -!- PTM: Sumoylation enhances its transcriptional activity and interaction CC with ESR1, resulting in up-regulation of ESR1 activity. Estrogen CC stimulates sumoylation. Desumoylation by SENP1 negatively regulates its CC transcriptional activity. Sumoylation stimulates cell proliferation and CC increases the proportion of S phase cells in breast cancer cell lines. CC {ECO:0000269|PubMed:23160374}. CC -!- PTM: Undergoes lysosome-mediated degradation in a time-dependent manner CC in the liver. {ECO:0000250|UniProtKB:O08785}. CC -!- MISCELLANEOUS: CLOCK-BMAL1 double mutations within the PAS domains CC result in synergistic desensitization to high levels of CRY on CC repression of CLOCK-BMAL1 transcriptional activity of PER1 and disrupt CC circadian rhythmicity. CC -!- SEQUENCE CAUTION: CC Sequence=BAA20792.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; 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; AF011568; AAB83969.1; -; mRNA. DR EMBL; AH008440; AAF13733.1; -; Genomic_DNA. DR EMBL; EF015897; ABM64208.1; -; Genomic_DNA. DR EMBL; AB002332; BAA20792.2; ALT_INIT; mRNA. DR EMBL; AK291708; BAF84397.1; -; mRNA. DR EMBL; BC126157; AAI26158.1; -; mRNA. DR EMBL; BC126159; AAI26160.1; -; mRNA. DR EMBL; AB005535; BAA21774.1; -; mRNA. DR CCDS; CCDS3500.1; -. DR RefSeq; NP_001254772.1; NM_001267843.1. DR RefSeq; NP_004889.1; NM_004898.3. DR RefSeq; XP_005265844.1; XM_005265787.2. DR RefSeq; XP_011532711.1; XM_011534409.2. DR RefSeq; XP_011532712.1; XM_011534410.2. DR RefSeq; XP_011532713.1; XM_011534411.2. DR RefSeq; XP_016864343.1; XM_017008854.1. DR PDB; 4H10; X-ray; 2.40 A; B=29-89. DR PDB; 6QPJ; X-ray; 2.31 A; A=105-265. DR PDBsum; 4H10; -. DR PDBsum; 6QPJ; -. DR AlphaFoldDB; O15516; -. DR SMR; O15516; -. DR BioGRID; 114944; 86. DR ComplexPortal; CPX-3229; CLOCK-BMAL1 transcription complex. DR ComplexPortal; CPX-3230; CLOCK-BMAL2 transcription complex. DR CORUM; O15516; -. DR DIP; DIP-46009N; -. DR IntAct; O15516; 17. DR MINT; O15516; -. DR STRING; 9606.ENSP00000426983; -. DR GlyCosmos; O15516; 1 site, 1 glycan. DR GlyGen; O15516; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O15516; -. DR PhosphoSitePlus; O15516; -. DR BioMuta; CLOCK; -. DR EPD; O15516; -. DR jPOST; O15516; -. DR MassIVE; O15516; -. DR MaxQB; O15516; -. DR PaxDb; 9606-ENSP00000308741; -. DR PeptideAtlas; O15516; -. DR ProteomicsDB; 48706; -. DR Antibodypedia; 909; 607 antibodies from 41 providers. DR DNASU; 9575; -. DR Ensembl; ENST00000309964.8; ENSP00000308741.4; ENSG00000134852.15. DR Ensembl; ENST00000381322.5; ENSP00000370723.1; ENSG00000134852.15. DR Ensembl; ENST00000513440.6; ENSP00000426983.1; ENSG00000134852.15. DR GeneID; 9575; -. DR KEGG; hsa:9575; -. DR MANE-Select; ENST00000513440.6; ENSP00000426983.1; NM_004898.4; NP_004889.1. DR UCSC; uc003haz.3; human. DR AGR; HGNC:2082; -. DR CTD; 9575; -. DR DisGeNET; 9575; -. DR GeneCards; CLOCK; -. DR HGNC; HGNC:2082; CLOCK. DR HPA; ENSG00000134852; Low tissue specificity. DR MIM; 601851; gene. DR neXtProt; NX_O15516; -. DR OpenTargets; ENSG00000134852; -. DR PharmGKB; PA26609; -. DR VEuPathDB; HostDB:ENSG00000134852; -. DR eggNOG; KOG3561; Eukaryota. DR GeneTree; ENSGT00940000157580; -. DR HOGENOM; CLU_010044_2_2_1; -. DR InParanoid; O15516; -. DR OMA; HVPNSAH; -. DR OrthoDB; 2899615at2759; -. DR PhylomeDB; O15516; -. DR TreeFam; TF324568; -. DR BRENDA; 2.3.1.48; 2681. DR PathwayCommons; O15516; -. DR Reactome; R-HSA-1368108; BMAL1:CLOCK,NPAS2 activates circadian gene expression. DR Reactome; R-HSA-1989781; PPARA activates gene expression. DR Reactome; R-HSA-3214847; HATs acetylate histones. DR Reactome; R-HSA-400253; Circadian Clock. DR Reactome; R-HSA-9707616; Heme signaling. DR SignaLink; O15516; -. DR SIGNOR; O15516; -. DR BioGRID-ORCS; 9575; 12 hits in 1187 CRISPR screens. DR ChiTaRS; CLOCK; human. DR GeneWiki; CLOCK; -. DR GenomeRNAi; 9575; -. DR Pharos; O15516; Tbio. DR PRO; PR:O15516; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; O15516; Protein. DR Bgee; ENSG00000134852; Expressed in secondary oocyte and 211 other cell types or tissues. DR ExpressionAtlas; O15516; baseline and differential. DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB. DR GO; GO:0033391; C:chromatoid body; ISS:UniProtKB. DR GO; GO:0005694; C:chromosome; IDA:UniProtKB. DR GO; GO:1990513; C:CLOCK-BMAL transcription complex; IPI:ComplexPortal. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0031490; F:chromatin DNA binding; ISS:UniProtKB. DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISS:BHF-UCL. DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISS:UniProtKB. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISS:BHF-UCL. DR GO; GO:0070888; F:E-box binding; IDA:UniProtKB. DR GO; GO:0004402; F:histone acetyltransferase activity; IMP:UniProtKB. DR GO; GO:0046983; F:protein dimerization activity; IEA:InterPro. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:BHF-UCL. DR GO; GO:0043565; F:sequence-specific DNA binding; ISS:UniProtKB. DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL. DR GO; GO:0071479; P:cellular response to ionizing radiation; IDA:UniProtKB. DR GO; GO:0032922; P:circadian regulation of gene expression; IDA:UniProtKB. DR GO; GO:0007623; P:circadian rhythm; TAS:ProtInc. DR GO; GO:0000077; P:DNA damage checkpoint signaling; IMP:UniProtKB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; ISS:UniProtKB. DR GO; GO:2000323; P:negative regulation of glucocorticoid receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0009648; P:photoperiodism; TAS:ProtInc. DR GO; GO:0042753; P:positive regulation of circadian rhythm; IDA:ComplexPortal. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0050729; P:positive regulation of inflammatory response; IEA:Ensembl. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB. DR GO; GO:0006473; P:protein acetylation; IDA:UniProtKB. DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; ISS:UniProtKB. DR GO; GO:0042634; P:regulation of hair cycle; IMP:UniProtKB. DR GO; GO:0050796; P:regulation of insulin secretion; ISS:UniProtKB. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:2000074; P:regulation of type B pancreatic cell development; ISS:UniProtKB. DR GO; GO:0051775; P:response to redox state; IDA:UniProtKB. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB. DR CDD; cd19734; bHLH-PAS_CLOCK; 1. DR CDD; cd00130; PAS; 2. DR Gene3D; 4.10.280.10; Helix-loop-helix DNA-binding domain; 1. DR Gene3D; 3.30.450.20; PAS domain; 2. DR IDEAL; IID00430; -. DR InterPro; IPR011598; bHLH_dom. DR InterPro; IPR047230; CLOCK-like. DR InterPro; IPR036638; HLH_DNA-bd_sf. DR InterPro; IPR001067; Nuc_translocat. DR InterPro; IPR001610; PAC. DR InterPro; IPR000014; PAS. DR InterPro; IPR035965; PAS-like_dom_sf. DR InterPro; IPR013767; PAS_fold. DR PANTHER; PTHR46055; CIRCADIAN LOCOMOTER OUTPUT CYCLES PROTEIN KAPUT; 1. DR PANTHER; PTHR46055:SF2; CIRCADIAN LOCOMOTER OUTPUT CYCLES PROTEIN KAPUT; 1. DR Pfam; PF00010; HLH; 1. DR Pfam; PF00989; PAS; 1. DR Pfam; PF14598; PAS_11; 1. DR PRINTS; PR00785; NCTRNSLOCATR. DR SMART; SM00353; HLH; 1. DR SMART; SM00086; PAC; 1. DR SMART; SM00091; PAS; 2. DR SUPFAM; SSF47459; HLH, helix-loop-helix DNA-binding domain; 1. DR SUPFAM; SSF55785; PYP-like sensor domain (PAS domain); 2. DR PROSITE; PS50888; BHLH; 1. DR PROSITE; PS50112; PAS; 2. DR Genevisible; O15516; HS. PE 1: Evidence at protein level; KW 3D-structure; Activator; Acyltransferase; Biological rhythms; Cytoplasm; KW DNA damage; DNA-binding; Isopeptide bond; Nucleus; Phosphoprotein; KW Reference proteome; Repeat; Transcription; Transcription regulation; KW Transferase; Ubl conjugation. FT CHAIN 1..846 FT /note="Circadian locomoter output cycles protein kaput" FT /id="PRO_0000127163" FT DOMAIN 34..84 FT /note="bHLH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981" FT DOMAIN 107..177 FT /note="PAS 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140" FT DOMAIN 262..332 FT /note="PAS 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140" FT DOMAIN 336..379 FT /note="PAC" FT REGION 371..845 FT /note="Interaction with NR3C1" FT /evidence="ECO:0000250|UniProtKB:O08785" FT REGION 392..411 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 420..495 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 450..570 FT /note="Interaction with SIRT1" FT /evidence="ECO:0000250|UniProtKB:O08785" FT REGION 514..564 FT /note="Implicated in the circadian rhythmicity" FT /evidence="ECO:0000250" FT REGION 624..654 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 764..783 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 811..846 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 32..47 FT /note="Nuclear localization signal" FT /evidence="ECO:0000250|UniProtKB:O08785" FT COMPBIAS 427..464 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 475..495 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 39 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000269|PubMed:23229515" FT SITE 43 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000269|PubMed:23229515" FT SITE 47 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000269|PubMed:23229515" FT SITE 84 FT /note="Important for interaction with BMAL1" FT /evidence="ECO:0000269|PubMed:23229515" FT MOD_RES 38 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O08785" FT MOD_RES 42 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O08785" FT MOD_RES 408 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O08785" FT MOD_RES 427 FT /note="Phosphoserine; by GSK3-beta" FT /evidence="ECO:0000250|UniProtKB:O08785" FT MOD_RES 431 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O08785" FT MOD_RES 451 FT /note="Phosphothreonine; by CDK5" FT /evidence="ECO:0000269|PubMed:24235147" FT MOD_RES 461 FT /note="Phosphothreonine; by CDK5" FT /evidence="ECO:0000269|PubMed:24235147" FT CROSSLNK 67 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO1)" FT /evidence="ECO:0000250|UniProtKB:O08785" FT CROSSLNK 842 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO1)" FT /evidence="ECO:0000250|UniProtKB:O08785" FT VARIANT 208 FT /note="S -> C (in dbSNP:rs34897046)" FT /id="VAR_040061" FT VARIANT 380 FT /note="E -> K (in dbSNP:rs1056478)" FT /id="VAR_040062" FT VARIANT 395 FT /note="L -> I (in dbSNP:rs6855837)" FT /id="VAR_029076" FT VARIANT 542 FT /note="H -> R (in dbSNP:rs3762836)" FT /id="VAR_029077" FT MUTAGEN 38 FT /note="S->E: Phosphomimetic mutant with no effect on DNA FT binding or CLOCK-BMAL1 transcriptional activity." FT /evidence="ECO:0000269|PubMed:23229515" FT MUTAGEN 42 FT /note="S->E: Phosphomimetic mutant with no effect on DNA FT binding or CLOCK-BMAL1 transcriptional activity." FT /evidence="ECO:0000269|PubMed:23229515" FT MUTAGEN 50 FT /note="F->M: No effect on BMAL1 binding." FT /evidence="ECO:0000269|PubMed:23229515" FT MUTAGEN 84 FT /note="H->L: Impaired BMAL1 binding." FT /evidence="ECO:0000269|PubMed:23229515" FT MUTAGEN 116 FT /note="E->K: 3-fold increase in PER1 reporter activity by FT CLOCK-BMAL1. Some reduction of CRY1 inhibition of FT CLOCK-BMAL1 transcriptional activity; when associated with FT K-367 and L-601." FT /evidence="ECO:0000269|PubMed:16474406" FT MUTAGEN 332 FT /note="G->E: 3-fold increase in PER1 reporter activity by FT CLOCK-BMAL1. Some reduction of CRY1 inhibition of FT CLOCK-BMAL1 transcriptional activity; when associated with FT L-840." FT /evidence="ECO:0000269|PubMed:16474406" FT MUTAGEN 360 FT /note="H->Y: 3-fold increase in PER1 reporter activity by FT CLOCK-BMAL1. Some reduction of CRY1 inhibition of FT CLOCK-BMAL1 transcriptional activity." FT /evidence="ECO:0000269|PubMed:16474406" FT MUTAGEN 367 FT /note="E->K: 3-fold increase in PER1 reporter activity by FT CLOCK-BMAL1. Some reduction of CRY1 inhibition of FT CLOCK-BMAL1 transcriptional activity; when associated with FT E-116 and L-601." FT /evidence="ECO:0000269|PubMed:16474406" FT MUTAGEN 451 FT /note="T->F: Significant loss in phosphorylation." FT /evidence="ECO:0000269|PubMed:24235147" FT MUTAGEN 461 FT /note="T->F: Significant loss in phosphorylation." FT /evidence="ECO:0000269|PubMed:24235147" FT MUTAGEN 601 FT /note="V->L: 3-fold increase in PER1 reporter activity by FT CLOCK-BMAL1. Some reduction of CRY1 inhibition of FT CLOCK-BMAL1 transcriptional activity; when associated with FT K-116 and K-367." FT /evidence="ECO:0000269|PubMed:16474406" FT MUTAGEN 840 FT /note="P->L: 3-fold increase in PER1 reporter activity by FT CLOCK-BMAL1. Some reduction of CRY1 inhibition of FT CLOCK-BMAL1 transcriptional activity; when associated with FT E-332." FT /evidence="ECO:0000269|PubMed:16474406" FT CONFLICT 440 FT /note="S -> P (in Ref. 1; AAF13733)" FT /evidence="ECO:0000305" FT HELIX 33..58 FT /evidence="ECO:0007829|PDB:4H10" FT STRAND 61..63 FT /evidence="ECO:0007829|PDB:4H10" FT HELIX 70..89 FT /evidence="ECO:0007829|PDB:4H10" FT HELIX 107..118 FT /evidence="ECO:0007829|PDB:6QPJ" FT STRAND 120..126 FT /evidence="ECO:0007829|PDB:6QPJ" FT STRAND 130..134 FT /evidence="ECO:0007829|PDB:6QPJ" FT HELIX 138..142 FT /evidence="ECO:0007829|PDB:6QPJ" FT HELIX 146..149 FT /evidence="ECO:0007829|PDB:6QPJ" FT HELIX 154..156 FT /evidence="ECO:0007829|PDB:6QPJ" FT HELIX 160..162 FT /evidence="ECO:0007829|PDB:6QPJ" FT HELIX 163..174 FT /evidence="ECO:0007829|PDB:6QPJ" FT HELIX 182..184 FT /evidence="ECO:0007829|PDB:6QPJ" FT STRAND 191..198 FT /evidence="ECO:0007829|PDB:6QPJ" FT STRAND 210..221 FT /evidence="ECO:0007829|PDB:6QPJ" FT STRAND 249..257 FT /evidence="ECO:0007829|PDB:6QPJ" SQ SEQUENCE 846 AA; 95304 MW; C292B451A33E4CBF CRC64; MLFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF NVLIKELGSM LPGNARKMDK STVLQKSIDF LRKHKEITAQ SDASEIRQDW KPTFLSNEEF TQLMLEALDG FFLAIMTDGS IIYVSESVTS LLEHLPSDLV DQSIFNFIPE GEHSEVYKIL STHLLESDSL TPEYLKSKNQ LEFCCHMLRG TIDPKEPSTY EYVKFIGNFK SLNSVSSSAH NGFEGTIQRT HRPSYEDRVC FVATVRLATP QFIKEMCTVE EPNEEFTSRH SLEWKFLFLD HRAPPIIGYL PFEVLGTSGY DYYHVDDLEN LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW LQTHYYITYH QWNSRPEFIV CTHTVVSYAE VRAERRRELG IEESLPETAA DKSQDSGSDN RINTVSLKEA LERFDHSPTP SASSRSSRKS SHTAVSDPSS TPTKIPTDTS TPPRQHLPAH EKMVQRRSSF SSQSINSQSV GSSLTQPVMS QATNLPIPQG MSQFQFSAQL GAMQHLKDQL EQRTRMIEAN IHRQQEELRK IQEQLQMVHG QGLQMFLQQS NPGLNFGSVQ LSSGNSSNIQ QLAPINMQGQ VVPTNQIQSG MNTGHIGTTQ HMIQQQTLQS TSTQSQQNVL SGHSQQTSLP SQTQSTLTAP LYNTMVISQP AAGSMVQIPS SMPQNSTQSA AVTTFTQDRQ IRFSQGQQLV TKLVTAPVAC GAVMVPSTML MGQVVTAYPT FATQQQQSQT LSVTQQQQQQ SSQEQQLTSV QQPSQAQLTQ PPQQFLQTSR LLHGNPSTQL ILSAAFPLQQ STFPQSHHQQ HQSQQQQQLS RHRTDSLPDP SKVQPQ //