CLOCK_HUMAN
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 03-AUG-2022, entry version 213.
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 ARNTL; 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 ARNTL; 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 ARNTL 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, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and
CC CRY2) plays a critical role in rhythm generation, whereas delays
CC imposed by post-translational modifications (PTMs) are important for
CC determining the period (tau) of the rhythms (tau refers to the period
CC of a rhythm and is the length, in time, of one complete cycle). A
CC diurnal rhythm is synchronized with the day/night cycle, while the
CC ultradian and infradian rhythms have a period shorter and longer than
CC 24 hours, respectively. Disruptions in the circadian rhythms contribute
CC to the pathology of cardiovascular diseases, cancer, metabolic
CC syndromes and aging. A transcription/translation feedback loop (TTFL)
CC forms the core of the molecular circadian clock mechanism.
CC Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2,
CC form the positive limb of the feedback loop, act in the form of a
CC heterodimer and activate the transcription of core clock genes and
CC clock-controlled genes (involved in key metabolic processes), harboring
CC E-box elements (5'-CACGTG-3') within their promoters. The core clock
CC genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form
CC the negative limb of the feedback loop and interact with the
CC CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its
CC activity and thereby negatively regulating their own expression. This
CC heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G,
CC which form a second feedback loop and which activate and repress
CC ARNTL/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-
CC ARNTL/BMAL1 heterodimer regulates the circadian expression of
CC SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A,
CC PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10
CC and also genes implicated in glucose and lipid metabolism. Promotes
CC rhythmic chromatin opening, regulating the DNA accessibility of other
CC transcription factors. The CLOCK-ARNTL2/BMAL2 heterodimer activates the
CC transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding
CC motif for the CLOCK-ARNTL/BMAL1 heterodimer is 5'-CACGTGA-3', which
CC contains a flanking Ala residue in addition to the canonical 6-
CC nucleotide E-box sequence (PubMed:23229515). CLOCK specifically binds
CC to the half-site 5'-CAC-3', while ARNTL binds to the half-site 5'-GTGA-
CC 3' (PubMed:23229515). The CLOCK-ARNTL/BMAL1 heterodimer also recognizes
CC the non-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 ARNTL/BMAL1.
CC Represses glucocorticoid receptor NR3C1/GR-induced transcriptional
CC activity by reducing the association of NR3C1/GR to glucocorticoid
CC response elements (GREs) via the acetylation of multiple lysine
CC residues located in its hinge region (PubMed:21980503). The
CC acetyltransferase activity of CLOCK is as important as its
CC transcription activity in circadian control. Acetylates metabolic
CC enzymes IMPDH2 and NDUFA9 in a circadian manner. Facilitated by BMAL1,
CC rhythmically interacts and acetylates argininosuccinate synthase 1
CC (ASS1) leading to enzymatic inhibition of ASS1 as well as the circadian
CC oscillation of arginine biosynthesis and subsequent ureagenesis
CC (PubMed:28985504). Drives the circadian rhythm of blood pressure
CC through transcriptional activation of ATP1B1 (By similarity).
CC {ECO:0000250|UniProtKB:O08785, ECO:0000269|PubMed:14645221,
CC ECO:0000269|PubMed:18587630, ECO:0000269|PubMed:21659603,
CC ECO:0000269|PubMed:21980503, ECO:0000269|PubMed:22284746,
CC ECO:0000269|PubMed:23229515, ECO:0000269|PubMed:23785138,
CC ECO:0000269|PubMed:24005054, 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-
CC ARNTL/BMAL1 heterodimer; NADH and NADPH enhance the DNA-binding
CC activity of the heterodimer. PubMed:23229515 reports that NADH and
CC NADPH have no significant effect on DNA-binding activity of the CLOCK-
CC ARNTL/BMAL1 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, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D
CC and/or CSNK1E, TIMELESS and the PER proteins (By similarity). Interacts
CC with KMT2A; in a circadian manner (By similarity). Forms a heterodimer
CC with ARNTL/BMAL1 (PubMed:21613214, PubMed:23229515). The CLOCK-
CC ARNTL/BMAL1 heterodimer is required for E-box-dependent
CC transactivation, for CLOCK nuclear translocation and degradation, and
CC for phosphorylation of both CLOCK and ARNTL/BMAL1 (By similarity).
CC Interacts with NR3C1 in a ligand-dependent fashion (PubMed:21980503).
CC Interacts with ESR1 and estrogen stimulates this interaction
CC (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 ARNTL/BMAL1 heterodimer with PER or CRY inhibits transcription
CC activation (PubMed:21613214). Interaction of the CLOCK-ARNTL/BMAL1 with
CC CRY1 is independent of DNA but with PER2 is off DNA (PubMed:21613214).
CC The CLOCK-ARNTL/BMAL1 heterodimer interacts with GSK3B. Interacts with
CC KDM5A (PubMed:21960634). Interacts with MYBBP1A (By similarity).
CC Interacts with THRAP3 (By similarity). Interacts with MED1; this
CC interaction requires the presence of THRAP3 (By similarity). Interacts
CC with NCOA2 (By similarity). The CLOCK-ARNTL/BMAL1 heterodimer interacts
CC with PASD1 (PubMed:25936801). Interacts with ASS1 and IMPDH2; in a
CC circadian manner (PubMed:28985504). Interacts with NDUFA9
CC (PubMed:28985504). Interacts with PIWIL2 (via PIWI domain)
CC (PubMed:28903391). Interacts with HNF4A (PubMed:30530698).
CC {ECO:0000250|UniProtKB:O08785, ECO:0000269|PubMed:14645221,
CC ECO:0000269|PubMed:20861012, ECO:0000269|PubMed:21613214,
CC ECO:0000269|PubMed:21960634, ECO:0000269|PubMed:21980503,
CC ECO:0000269|PubMed:23160374, ECO:0000269|PubMed:23229515,
CC ECO:0000269|PubMed:24235147, ECO:0000269|PubMed:25936801,
CC ECO:0000269|PubMed:28903391, ECO:0000269|PubMed:28985504,
CC ECO:0000269|PubMed:30530698}.
CC -!- INTERACTION:
CC O15516; O00327: ARNTL; NbExp=4; IntAct=EBI-1794265, EBI-1794206;
CC O15516; O00327-8: ARNTL; NbExp=6; IntAct=EBI-1794265, EBI-11991546;
CC O15516; Q8WYA1-3: ARNTL2; 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 ARNTL/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-ARNTL/BMAL1 heterodimer thereby increasing CLOCK-ARNTL/BMAL1-
CC mediated transcriptional activation of PER1/2/3 and CRY1/2.
CC {ECO:0000250|UniProtKB:O08785}.
CC -!- PTM: Phosphorylation is dependent on the CLOCK-ARNTL/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-ARNTL/BMAL1 double mutations within the PAS
CC domains result in synergistic desensitization to high levels of CRY on
CC repression of CLOCK-ARNTL/BMAl1 transcriptional activity of PER1 and
CC disrupt circadian rhythmicity.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA20792.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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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; 81.
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.ENSP00000308741; -.
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; O15516; -.
DR PeptideAtlas; O15516; -.
DR PRIDE; O15516; -.
DR ProteomicsDB; 48706; -.
DR Antibodypedia; 909; 536 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 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; RPSYEEK; -.
DR OrthoDB; 205871at2759; -.
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; 11 hits in 1109 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 209 other tissues.
DR ExpressionAtlas; O15516; baseline and differential.
DR Genevisible; O15516; HS.
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:0005667; C:transcription regulator complex; IPI:MGI.
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:2000323; P:negative regulation of glucocorticoid receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; 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: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:0045944; P:positive regulation of transcription by RNA polymerase II; IGI:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA: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: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:0006355; P:regulation of transcription, DNA-templated; ISS:UniProtKB.
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; cd00130; PAS; 2.
DR Gene3D; 4.10.280.10; -; 1.
DR IDEAL; IID00430; -.
DR InterPro; IPR011598; bHLH_dom.
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 Pfam; PF00010; HLH; 1.
DR Pfam; PF00989; PAS; 1.
DR PRINTS; PR00785; NCTRNSLOCATR.
DR SMART; SM00353; HLH; 1.
DR SMART; SM00086; PAC; 1.
DR SMART; SM00091; PAS; 2.
DR SUPFAM; SSF47459; SSF47459; 1.
DR SUPFAM; SSF55785; SSF55785; 2.
DR PROSITE; PS50888; BHLH; 1.
DR PROSITE; PS50112; PAS; 2.
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 ARNTL/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-ARNTL/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-ARNTL/BMAL1 transcriptional activity."
FT /evidence="ECO:0000269|PubMed:23229515"
FT MUTAGEN 50
FT /note="F->M: No effect on ARNTL/BMAL1 binding."
FT /evidence="ECO:0000269|PubMed:23229515"
FT MUTAGEN 84
FT /note="H->L: Impaired ARNTL/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-ARNTL/BMAL1. Some reduction of CRY1 inhibition of
FT CLOCK-ARNTL/BMAL1 transcriptional activity; when associated
FT with 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-ARNTL/BMAL1. Some reduction of CRY1 inhibition of
FT CLOCK-ARNTL/BMAL1 transcriptional activity; when associated
FT with 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-ARNTL/BMAL1. Some reduction of CRY1 inhibition of
FT CLOCK-ARNTL/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-ARNTL/BMAL1. Some reduction of CRY1 inhibition of
FT CLOCK-ARNTL/BMAL1 transcriptional activity; when associated
FT with 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-ARNTL/BMAL1. Some reduction of CRY1 inhibition of
FT CLOCK-ARNTL/BMAL1 transcriptional activity; when associated
FT with 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-ARNTL/BMAL1. Some reduction of CRY1 inhibition of
FT CLOCK-ARNTL/BMAL1 transcriptional activity; when associated
FT with 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
