ID CLOCK_RAT Reviewed; 862 AA. AC Q9WVS9; Q920Y1; DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1999, sequence version 1. DT 08-NOV-2023, entry version 159. DE RecName: Full=Circadian locomoter output cycles protein kaput; DE Short=rCLOCK; DE EC=2.3.1.48; GN Name=Clock; OS Rattus norvegicus (Rat). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY, AND RP INDUCTION. RC TISSUE=Brain; RX PubMed=10095082; DOI=10.1016/s0169-328x(99)00031-5; RA Abe H., Honma S., Namihira M., Tanahashi Y., Ikeda M., Yu W., Honma K.; RT "Phase-dependent induction by light of rat Clock gene expression in the RT suprachiasmatic nucleus."; RL Brain Res. Mol. Brain Res. 66:104-110(1999). 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. CLOCK specifically binds to the half-site 5'-CAC-3', while CC BMAL1 binds to the half-site 5'-GTGA-3'. The CLOCK-BMAL1 heterodimer CC also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'- CC CATGTGA-3'. CLOCK has an intrinsic acetyltransferase activity, which CC enables circadian chromatin remodeling by acetylating histones and CC 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. The acetyltransferase activity of CLOCK is as CC important as its transcription activity in circadian control. CC Acetylates metabolic enzymes IMPDH2 and NDUFA9 in a circadian manner. CC 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 (By similarity). Drives the circadian rhythm of CC blood pressure through transcriptional activation of ATP1B1 (By CC similarity). {ECO:0000250|UniProtKB:O08785, CC ECO:0000250|UniProtKB:O15516}. 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 -!- 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). Forms a heterodimer with CC BMAL1 (By similarity). The CLOCK-BMAL1 heterodimer is required for E- CC box-dependent transactivation, for CLOCK nuclear translocation and CC degradation, and for phosphorylation of both CLOCK and BMAL1 (By CC similarity). Interacts with NR3C1 in a ligand-dependent fashion (By CC similarity). Interacts with ESR1 and estrogen stimulates this CC interaction (By similarity). Interacts with the complex p35/CDK5 (By CC similarity). Interacts with RELA/p65 (By similarity). Interacts with CC KAT2B, CREBBP and EP300 (By similarity). Interacts with ID1 and ID3 (By CC similarity). Interacts with ID2 (By similarity). Interacts with MTA1 CC (By similarity). Interacts with OGA (By similarity). Interacts with CC SIRT1 (By similarity). Interacts with CIPC (By similarity). Interacts CC with EZH2 (By similarity). Interacts with EIF4E, PIWIL1 and DDX4 (By CC similarity). Interacts with PER1, PER2, CRY1 and CRY2 and this CC interaction requires a translocation to the nucleus (By similarity). CC Interaction of the CLOCK-BMAL1 heterodimer with PER or CRY inhibits CC transcription activation (By similarity). Interaction of the CLOCK- CC BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA (By CC similarity). The CLOCK-BMAL1 heterodimer interacts with GSK3B (By CC similarity). Interacts with KDM5A (By similarity). Interacts with CC KMT2A; in a circadian manner (By similarity). Interacts with MYBBP1A CC (By similarity). Interacts with THRAP3 (By similarity). Interacts with CC MED1; this interaction requires the presence of THRAP3 (By similarity). CC Interacts with NCOA2 (By similarity). The CLOCK-BMAL1 heterodimer CC interacts with PASD1. Interacts with ASS1 and IMPDH2; in a circadian CC manner. Interacts with NDUFA9 (By similarity). Interacts with PIWIL2 CC (via PIWI domain) (By similarity). Interacts with HNF4A (By CC similarity). {ECO:0000250|UniProtKB:O08785, CC ECO:0000250|UniProtKB:O15516}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:O08785}. Nucleus CC {ECO:0000255|PROSITE-ProRule:PRU00981}. Cytoplasm, cytosol CC {ECO:0000250|UniProtKB:O15516}. Note=Localizes to sites of DNA damage CC in a H2AX-independent manner. Shuttling between the cytoplasm and the CC 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. {ECO:0000250|UniProtKB:O08785, CC ECO:0000250|UniProtKB:O15516}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; Synonyms=Long, Clock-L; CC IsoId=Q9WVS9-1; Sequence=Displayed; CC Name=2; Synonyms=Short, Clock-S; CC IsoId=Q9WVS9-2; Sequence=VSP_021795; CC -!- TISSUE SPECIFICITY: Expressed in the suprachiasmatic nucleus (SCN), and CC in the piriform cortex (PC). {ECO:0000269|PubMed:10095082}. CC -!- INDUCTION: Without light exposure, high levels at ZT6 and low levels at CC ZT18 and ZT22. Light exposure increases levels in the SCN in phase CC dependent manner. Levels increased significantly during the subjective CC night (ZT10-20). In the piriform cortex, levels increased by light at CC ZT14. {ECO:0000269|PubMed:10095082}. 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:0000250|UniProtKB:O08785}. 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. {ECO:0000250|UniProtKB:O08785}. CC -!- PTM: Undergoes lysosome-mediated degradation in a time-dependent manner CC in the liver. {ECO:0000250|UniProtKB:O08785}. 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; AB019258; BAA81819.1; -; mRNA. DR EMBL; AB019259; BAB68768.1; -; mRNA. DR RefSeq; NP_001276761.1; NM_001289832.1. DR RefSeq; NP_068628.1; NM_021856.2. DR AlphaFoldDB; Q9WVS9; -. DR SMR; Q9WVS9; -. DR STRING; 10116.ENSRNOP00000002976; -. DR iPTMnet; Q9WVS9; -. DR PhosphoSitePlus; Q9WVS9; -. DR PaxDb; 10116-ENSRNOP00000002976; -. DR PeptideAtlas; Q9WVS9; -. DR GeneID; 60447; -. DR KEGG; rno:60447; -. DR UCSC; RGD:620271; rat. [Q9WVS9-1] DR AGR; RGD:620271; -. DR CTD; 9575; -. DR RGD; 620271; Clock. DR eggNOG; KOG3561; Eukaryota. DR InParanoid; Q9WVS9; -. DR OrthoDB; 2899615at2759; -. DR PhylomeDB; Q9WVS9; -. DR PRO; PR:Q9WVS9; -. DR Proteomes; UP000002494; Unplaced. DR GO; GO:0033391; C:chromatoid body; ISS:UniProtKB. DR GO; GO:0005694; C:chromosome; ISO:RGD. DR GO; GO:1990513; C:CLOCK-BMAL transcription complex; ISO:RGD. DR GO; GO:0005737; C:cytoplasm; ISO:RGD. DR GO; GO:0005829; C:cytosol; ISS:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005726; C:perichromatin fibrils; IDA:RGD. DR GO; GO:0005667; C:transcription regulator complex; ISS:UniProtKB. DR GO; GO:0031490; F:chromatin DNA binding; ISS:UniProtKB. DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISO:RGD. 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; ISO:RGD. DR GO; GO:0070888; F:E-box binding; ISS:UniProtKB. DR GO; GO:0004402; F:histone acetyltransferase activity; ISS: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; ISS:UniProtKB. DR GO; GO:0043565; F:sequence-specific DNA binding; ISS:UniProtKB. DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:RGD. DR GO; GO:0071479; P:cellular response to ionizing radiation; ISO:RGD. DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB. DR GO; GO:0007623; P:circadian rhythm; IEP:RGD. DR GO; GO:0000077; P:DNA damage checkpoint signaling; ISO:RGD. DR GO; GO:0009649; P:entrainment of circadian clock; IEP:RGD. DR GO; GO:0007565; P:female pregnancy; IEP:RGD. 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:0042753; P:positive regulation of circadian rhythm; ISO:RGD. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0050729; P:positive regulation of inflammatory response; ISO:RGD. 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; ISO:RGD. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB. DR GO; GO:0006473; P:protein acetylation; ISS: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; ISS: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:0009416; P:response to light stimulus; IEP:RGD. DR GO; GO:0051775; P:response to redox state; ISS:UniProtKB. 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 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. PE 2: Evidence at transcript level; KW Activator; Alternative splicing; Biological rhythms; Cytoplasm; DNA damage; KW DNA-binding; Isopeptide bond; Nucleus; Phosphoprotein; Reference proteome; KW Repeat; Transcription; Transcription regulation; Transferase; KW Ubl conjugation. FT CHAIN 1..862 FT /note="Circadian locomoter output cycles protein kaput" FT /id="PRO_0000262638" 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..861 FT /note="Interaction with NR3C1" FT /evidence="ECO:0000250|UniProtKB:O08785" FT REGION 388..497 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 623..652 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 768..802 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 822..862 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 400..415 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 427..457 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 474..497 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 822..840 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 39 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000250|UniProtKB:O15516" FT SITE 43 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000250|UniProtKB:O15516" FT SITE 47 FT /note="Interaction with E-box DNA" FT /evidence="ECO:0000250|UniProtKB:O15516" FT SITE 84 FT /note="Important for interaction with BMAL1" FT /evidence="ECO:0000250|UniProtKB:O15516" 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:0000250|UniProtKB:O15516" FT MOD_RES 461 FT /note="Phosphothreonine; by CDK5" FT /evidence="ECO:0000250|UniProtKB:O15516" 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 858 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO1)" FT /evidence="ECO:0000250|UniProtKB:O08785" FT VAR_SEQ 484..513 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:10095082" FT /id="VSP_021795" SQ SEQUENCE 862 AA; 97004 MW; D031E4A3758907EC CRC64; MLFTVSCSKM SSIVDRDDSS IFDGLVEEDD KDKAKRVSRN KSEKKRRDQF NVLIKELGSM LPGNARKMDK STVLQKSIDF LRKHKEITAQ SDASEIRQDW KPTFLSNEEF TQLMLEALDG FFLAIMTDGS IIYVSETVTS LLEHLPSDLV DQSIFNFIPE GEHSEVYKIL STHLLESDSL TPEDLKSKNQ LEFCCHMLRG TIDPKEPSTY EYVRFIGNFK SLNSVSTSTH NGFEGTIQRT HRPSYEDRVC FVATVRLATP QFIKEMCTVE EPNEEFTSRH SLEWKFLFLD HRAPPIIGYL PFEVLGTSGY DYYHVDDLES LAKCHEHLMQ YGKGKSCYYR FLTKGQQWIW LQTHYYITYH QWNSRPEFIV CTHTVVSYAE VRAERRRELG VEESLPETAA DKSQDSGSDN RINTVSLKEA LERFDHSPTP SASSRSSRKS SHTAVSDPSS TPTKIPTDTS TPPRPHLPAH EKMTQRRSSF SSQSINSQSV GSSLTQPAMS QAANLPIPQG MSQFQLSAQL GAMQHLKDQL EQRTRMIEAN IHRQQEELRK IQEQLQMVHG QGLQMFLQQS NPGLNLGSVQ LSSGNSNIQQ LTPINMQGQV VPVNQIQSGV NAGHVSTGQH MIQQQTLQST STQSQQSVMS GHSQPTSLPN QTPSTLTAPL YNTMVISQPA AGSMVPIPSS MPQNSTQSAT VTTFTQDRQI RFSQGQQLVT KLVTAPVACG AVMVPSTMLM GQVVTAYPTF ATQQQQAQAL SVTQQQQQQQ QQQQQQQQQQ PQQAQQPQSQ QSSQDQPHPS VQQPAQLTQP PQQFLQTSRL LHGNPSTQLI LSAAFPLQQS TFPPSHHQQH QQQQLHRHRT DSLTDPSKVQ PQ //