ID   FRQ_NEUCR               Reviewed;         989 AA.
AC   P19970; Q01276; Q7RVB1; V5IKG2; V5IL36;
DT   01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT   07-JUN-2005, sequence version 3.
DT   24-JAN-2024, entry version 128.
DE   RecName: Full=Frequency clock protein;
GN   Name=frq; ORFNames=B13D24.170, NCU02265;
OS   Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 /
OS   FGSC 987).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC   Sordariomycetidae; Sordariales; Sordariaceae; Neurospora.
OX   NCBI_TaxID=367110;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND MUTAGENESIS OF GLU-364; GLY-459; GLY-482
RP   AND ALA-895.
RC   STRAIN=ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987;
RX   PubMed=8052643; DOI=10.1073/pnas.91.16.7683;
RA   Aronson B.D., Johnson K.A., Dunlap J.C.;
RT   "Circadian clock locus frequency: protein encoded by a single open reading
RT   frame defines period length and temperature compensation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 91:7683-7687(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987;
RX   PubMed=12655011; DOI=10.1093/nar/gkg293;
RA   Mannhaupt G., Montrone C., Haase D., Mewes H.-W., Aign V., Hoheisel J.D.,
RA   Fartmann B., Nyakatura G., Kempken F., Maier J., Schulte U.;
RT   "What's in the genome of a filamentous fungus? Analysis of the Neurospora
RT   genome sequence.";
RL   Nucleic Acids Res. 31:1944-1954(2003).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987;
RX   PubMed=12712197; DOI=10.1038/nature01554;
RA   Galagan J.E., Calvo S.E., Borkovich K.A., Selker E.U., Read N.D.,
RA   Jaffe D.B., FitzHugh W., Ma L.-J., Smirnov S., Purcell S., Rehman B.,
RA   Elkins T., Engels R., Wang S., Nielsen C.B., Butler J., Endrizzi M.,
RA   Qui D., Ianakiev P., Bell-Pedersen D., Nelson M.A., Werner-Washburne M.,
RA   Selitrennikoff C.P., Kinsey J.A., Braun E.L., Zelter A., Schulte U.,
RA   Kothe G.O., Jedd G., Mewes H.-W., Staben C., Marcotte E., Greenberg D.,
RA   Roy A., Foley K., Naylor J., Stange-Thomann N., Barrett R., Gnerre S.,
RA   Kamal M., Kamvysselis M., Mauceli E.W., Bielke C., Rudd S., Frishman D.,
RA   Krystofova S., Rasmussen C., Metzenberg R.L., Perkins D.D., Kroken S.,
RA   Cogoni C., Macino G., Catcheside D.E.A., Li W., Pratt R.J., Osmani S.A.,
RA   DeSouza C.P.C., Glass N.L., Orbach M.J., Berglund J.A., Voelker R.,
RA   Yarden O., Plamann M., Seiler S., Dunlap J.C., Radford A., Aramayo R.,
RA   Natvig D.O., Alex L.A., Mannhaupt G., Ebbole D.J., Freitag M., Paulsen I.,
RA   Sachs M.S., Lander E.S., Nusbaum C., Birren B.W.;
RT   "The genome sequence of the filamentous fungus Neurospora crassa.";
RL   Nature 422:859-868(2003).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 202-989.
RX   PubMed=2525233; DOI=10.1038/339558a0;
RA   McClung C.R., Fox B.A., Dunlap J.C.;
RT   "The Neurospora clock gene frequency shares a sequence element with the
RT   Drosophila clock gene period.";
RL   Nature 339:558-562(1989).
RN   [5]
RP   PHOSPHORYLATION AT THR-501; SER-513 AND SER-519, AND MUTAGENESIS OF
RP   501-THR--SER-503; 513-SER-THR-514 AND SER-519.
RX   PubMed=10618401; DOI=10.1073/pnas.97.1.234;
RA   Liu Y., Loros J., Dunlap J.C.;
RT   "Phosphorylation of the Neurospora clock protein frequency determines its
RT   degradation rate and strongly influences the period length of the circadian
RT   clock.";
RL   Proc. Natl. Acad. Sci. U.S.A. 97:234-239(2000).
RN   [6]
RP   PHOSPHORYLATION BY CK2.
RX   PubMed=11959847; DOI=10.1101/gad.965102;
RA   Yang Y., Cheng P., Liu Y.;
RT   "Regulation of the Neurospora circadian clock by casein kinase II.";
RL   Genes Dev. 16:994-1006(2002).
CC   -!- FUNCTION: Circadian clock component involved in the generation of
CC       biological rhythms, in particular in rhythm stability, period length,
CC       and temperature compensation. Oscillates in abundance with a daily peak
CC       early in the morning. Behaves as a negative element in circadian
CC       transcriptional loop. May bind to wc-2 protein. The complex frq-wc-2
CC       may turn off the expression of frq.
CC   -!- INTERACTION:
CC       P19970; Q873J5: B9B11.040; Xeno; NbExp=2; IntAct=EBI-6995022, EBI-15874858;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000305}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative initiation; Named isoforms=2;
CC       Name=Long;
CC         IsoId=P19970-1; Sequence=Displayed;
CC       Name=Short;
CC         IsoId=P19970-2; Sequence=VSP_018781;
CC   -!- INDUCTION: By light; perhaps through white collar-1 (wc-1) and white
CC       collar-2 (wc-2). Also activated directly by wc-1 and wc-2.
CC   -!- PTM: Progressive phosphorylation during the late circadian day and
CC       early night. Phosphorylation is also involved in regulating frq
CC       degradation. Phosphorylation by CKII may have at least three functions;
CC       it decreases the stability of frq, reduces the protein complex
CC       formation between frq and the white collar proteins, and is important
CC       for the closing of the Neurospora circadian negative feedback loop.
CC       {ECO:0000269|PubMed:10618401, ECO:0000269|PubMed:11959847}.
CC   -!- MISCELLANEOUS: [Isoform Long]: Maintains rhythms at high temperature
CC       (30 degrees Celsius).
CC   -!- MISCELLANEOUS: [Isoform Short]: Maintains rhythms at lower temperature
CC       (18 degrees Celsius). {ECO:0000305}.
CC   -!- SIMILARITY: Belongs to the FRQ family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=Ref.4; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR   EMBL; U17073; AAA57121.1; -; mRNA.
DR   EMBL; BX908789; CAF05882.1; -; Genomic_DNA.
DR   EMBL; CM002242; ESA42013.1; -; Genomic_DNA.
DR   EMBL; CM002242; ESA42014.1; -; Genomic_DNA.
DR   EMBL; CM002242; ESA42015.1; -; Genomic_DNA.
DR   PIR; T46659; T46659.
DR   RefSeq; XP_011395124.1; XM_011396822.1. [P19970-2]
DR   RefSeq; XP_011395125.1; XM_011396823.1. [P19970-1]
DR   RefSeq; XP_011395126.1; XM_011396824.1. [P19970-1]
DR   AlphaFoldDB; P19970; -.
DR   DIP; DIP-41987N; -.
DR   IntAct; P19970; 2.
DR   MINT; P19970; -.
DR   STRING; 367110.P19970; -.
DR   iPTMnet; P19970; -.
DR   PaxDb; 5141-EFNCRP00000003120; -.
DR   EnsemblFungi; ESA42013; ESA42013; NCU02265. [P19970-1]
DR   EnsemblFungi; ESA42014; ESA42014; NCU02265. [P19970-1]
DR   EnsemblFungi; ESA42015; ESA42015; NCU02265. [P19970-2]
DR   GeneID; 3876095; -.
DR   KEGG; ncr:NCU02265; -.
DR   VEuPathDB; FungiDB:NCU02265; -.
DR   HOGENOM; CLU_007103_1_0_1; -.
DR   InParanoid; P19970; -.
DR   OMA; VVPDDHF; -.
DR   OrthoDB; 1423897at2759; -.
DR   Proteomes; UP000001805; Chromosome 7, Linkage Group VII.
DR   GO; GO:0005737; C:cytoplasm; IEA:InterPro.
DR   GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0007623; P:circadian rhythm; IEA:InterPro.
DR   GO; GO:0006355; P:regulation of DNA-templated transcription; IEA:InterPro.
DR   InterPro; IPR018554; FRQ.
DR   Pfam; PF09421; FRQ; 1.
PE   1: Evidence at protein level;
KW   Alternative initiation; Biological rhythms; Nucleus; Phosphoprotein;
KW   Reference proteome; Transcription; Transcription regulation.
FT   CHAIN           1..989
FT                   /note="Frequency clock protein"
FT                   /id="PRO_0000021288"
FT   REGION          1..139
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          208..290
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          331..445
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          524..642
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          865..907
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          968..989
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           564..568
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000255"
FT   COMPBIAS        23..43
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        44..91
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        94..117
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        231..290
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        385..428
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        546..572
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        598..636
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        867..885
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        970..989
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         501
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:10618401"
FT   MOD_RES         513
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:10618401"
FT   MOD_RES         519
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:10618401"
FT   VAR_SEQ         1..99
FT                   /note="Missing (in isoform Short)"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_018781"
FT   MUTAGEN         364
FT                   /note="E->K: In FRQ3; lengthened period."
FT                   /evidence="ECO:0000269|PubMed:8052643"
FT   MUTAGEN         459
FT                   /note="G->D: In FRQ7; lengthened period."
FT                   /evidence="ECO:0000269|PubMed:8052643"
FT   MUTAGEN         482
FT                   /note="G->S: In FRQ1; shortened period."
FT                   /evidence="ECO:0000269|PubMed:8052643"
FT   MUTAGEN         501..503
FT                   /note="TPS->APG: In FRQ10; no effect."
FT                   /evidence="ECO:0000269|PubMed:10618401"
FT   MUTAGEN         513..514
FT                   /note="ST->RA: In FRQ10; strong reduction in the
FT                   degradation rate; lengthened period."
FT                   /evidence="ECO:0000269|PubMed:10618401"
FT   MUTAGEN         513
FT                   /note="S->D: In FRQ10; reduces phosphorylation; slight
FT                   reduction in the degradation rate; loss of rhythmicity."
FT   MUTAGEN         513
FT                   /note="S->I: In FRQ10; reduces phosphorylation; strong
FT                   reduction in the degradation rate; lengthened period."
FT   MUTAGEN         519
FT                   /note="S->A: In FRQ10; no effect."
FT                   /evidence="ECO:0000269|PubMed:10618401"
FT   MUTAGEN         663..989
FT                   /note="Missing: In FRQ9; loss of rhythmicity."
FT   MUTAGEN         895
FT                   /note="A->T: In FRQ2; shortened period."
FT                   /evidence="ECO:0000269|PubMed:8052643"
FT   CONFLICT        146
FT                   /note="S -> T (in Ref. 1; AAA57121)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        202..207
FT                   /note="EATLRD -> MGGNRP (in Ref. 4)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        207
FT                   /note="D -> H (in Ref. 1; AAA57121)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        233
FT                   /note="H -> Y (in Ref. 1; AAA57121)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        962..963
FT                   /note="ML -> IV (in Ref. 1; AAA57121 and 4)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   989 AA;  108200 MW;  EC4E984FAD39F095 CRC64;
     MADSGDKSQG MRPPPFDSRG HPLPRRASPD KSITLENHRL ARDTSSRVTS SSALGVTESQ
     PQLKSSPTRR NSSGESEPTN WFNQSNRNPA AAFHDESHIM EVDPPFYQKE TDSSNEESRY
     PPGRNPVHPP GGVQLPGFRP VAAHSSAADD YRSVIDDLTV ENKRLKEELK RYKQFGSDVM
     RKEKLFEIKV HGLPRRKKRE LEATLRDFAA SLGDSSESTS QRRKTGRHGT AVHSSGVSLS
     KHDSSSSSRS RPVDSAYNSM STGRSSHAPH SSGPSLGRPS LTRAKSVGTQ KVENYLRDTP
     DGLLPHHIVM TDKEKKKLVV RRLEQLFTGK ISGRNMQRNQ SMPSMDAPLA PEGTNMAPPR
     PPPEGLREAC IQLQDGDNPR KNRSSKDNGS ASNSGGDQTE LGGTGTGSGD GSGSGGRTGN
     NTSPPGAIAP DQRPTRPRDL DPDRVQIPSE NMDYIRHLGL VSPEFLQGSR TSYQDVAPDA
     EGWVYLNLLC NLAQLHMVNV TPSFIRQAVS EKSTKFQLSA DGRKIRWRGG TDGTKFSSDS
     SEDKSQQSPM TEDTEDGSDK NGRRKKRKTQ QASSEIGRFG PSRSPSDTFH YKPMFVHRNS
     SSIETSLEES MSQGSEDAVD ESNMGNSKWD FSGSGTTQQR RKRRYDGAIV YYTGAPFCTD
     LSGDPGDMSP TAQMTAGREV EGSGSGDEVE HVLQRTLSGS SLPIRPLSDD RARVAEVLDF
     DPGNPPELVA DDGSSPNDED FVFPWCEDPA KVRIQPIAKE VMEPSGLGGV LPDDHFVMLV
     TTRRVVRPIL QRQLSRSTTS EDTAEFIAER LAAIRTSSPL PPRSHRLTVA PLQVEYVSGQ
     FRRLNPAPLP PPAIFYPPFS TDSSWDDGDD LASDDEEVEE VEEDSYSEGQ ISRRANPHFS
     DNNTYMRKDD LAFDTETDVR MDSDDNRLSD SGHNMRAMMP RAEAVDGDDS PLAAVTGKEV
     DMLHTGSSVA TAGGAESGYS SSMEDVSSS
//