CRF_HUMAN
ID CRF_HUMAN Reviewed; 196 AA.
AC P06850; B3KQS4;
DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1988, sequence version 1.
DT 03-AUG-2022, entry version 204.
DE RecName: Full=Corticoliberin;
DE AltName: Full=Corticotropin-releasing factor;
DE Short=CRF;
DE AltName: Full=Corticotropin-releasing hormone;
DE Flags: Precursor;
GN Name=CRH;
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], AND AMIDATION AT ILE-194.
RX PubMed=6605851; DOI=10.1002/j.1460-2075.1983.tb01499.x;
RA Shibahara S., Morimoto Y., Furutani Y., Notake M., Takahashi H.,
RA Shimizu S., Horikawa S., Numa S.;
RT "Isolation and sequence analysis of the human corticotropin-releasing
RT factor precursor gene.";
RL EMBO J. 2:775-779(1983).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RX PubMed=2783917; DOI=10.1016/0303-7207(89)90128-7;
RA Robinson B.G., D'Angio L.A. Jr., Pasieka K.B., Majzoub J.A.;
RT "Preprocorticotropin releasing hormone: cDNA sequence and in vitro
RT processing.";
RL Mol. Cell. Endocrinol. 61:175-180(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX PubMed=16303743; DOI=10.1093/dnares/12.2.117;
RA Otsuki T., Ota T., Nishikawa T., Hayashi K., Suzuki Y., Yamamoto J.,
RA Wakamatsu A., Kimura K., Sakamoto K., Hatano N., Kawai Y., Ishii S.,
RA Saito K., Kojima S., Sugiyama T., Ono T., Okano K., Yoshikawa Y.,
RA Aotsuka S., Sasaki N., Hattori A., Okumura K., Nagai K., Sugano S.,
RA Isogai T.;
RT "Signal sequence and keyword trap in silico for selection of full-length
RT human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA
RT libraries.";
RL DNA Res. 12:117-126(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [7]
RP PROTEIN SEQUENCE OF 154-186, AND TISSUE SPECIFICITY.
RX PubMed=3262120; DOI=10.1210/jcem-67-4-768;
RA Sasaki A., Tempst P., Liotta A.S., Margioris A.N., Hood L.E., Kent S.B.,
RA Sato S., Shinkawa O., Yoshinaga K., Krieger D.T.;
RT "Isolation and characterization of a corticotropin-releasing hormone-like
RT peptide from human placenta.";
RL J. Clin. Endocrinol. Metab. 67:768-773(1988).
RN [8]
RP STRUCTURE BY NMR OF 154-194.
RX PubMed=8386360; DOI=10.1093/protein/6.2.149;
RA Romier C., Bernassau J.-M., Cambillau C., Darbon H.;
RT "Solution structure of human corticotropin releasing factor by 1H NMR and
RT distance geometry with restrained molecular dynamics.";
RL Protein Eng. 6:149-156(1993).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (1.96 ANGSTROMS) OF 175-194 IN COMPLEX WITH CRFR1,
RP SUBUNIT, AND MUTAGENESIS OF GLN-183; ASN-187; ARG-188; LEU-190; MET-191 AND
RP GLU-192.
RX PubMed=18801728; DOI=10.1074/jbc.m805749200;
RA Pioszak A.A., Parker N.R., Suino-Powell K., Xu H.E.;
RT "Molecular recognition of corticotropin-releasing factor by its G-protein-
RT coupled receptor CRFR1.";
RL J. Biol. Chem. 283:32900-32912(2008).
RN [10]
RP VARIANT ARG-30, AND CHARACTERIZATION OF VARIANT ARG-30.
RX PubMed=23593457; DOI=10.1371/journal.pone.0061306;
RA Sansoni V., Forcella M., Mozzi A., Fusi P., Ambrosini R.,
RA Ferini-Strambi L., Combi R.;
RT "Functional characterization of a CRH missense mutation identified in an
RT ADNFLE family.";
RL PLoS ONE 8:E61306-E61306(2013).
CC -!- FUNCTION: Hormone regulating the release of corticotropin from
CC pituitary gland (By similarity). Induces NLRP6 in intestinal epithelial
CC cells, hence may influence gut microbiota profile (By similarity).
CC {ECO:0000250|UniProtKB:P06296, ECO:0000250|UniProtKB:Q8CIT0}.
CC -!- SUBUNIT: Interacts (via C-terminus) with CRFR1 (via N-terminal
CC extracellular domain). {ECO:0000269|PubMed:18801728}.
CC -!- INTERACTION:
CC P06850; P34998: CRHR1; NbExp=5; IntAct=EBI-3870390, EBI-3870393;
CC P06850; Q13324-1: CRHR2; NbExp=4; IntAct=EBI-3870390, EBI-26585317;
CC P06850; P48730-2: CSNK1D; NbExp=3; IntAct=EBI-3870390, EBI-9087876;
CC P06850; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-3870390, EBI-3867333;
CC P06850; Q15323: KRT31; NbExp=3; IntAct=EBI-3870390, EBI-948001;
CC P06850; Q8IUG1: KRTAP1-3; NbExp=3; IntAct=EBI-3870390, EBI-11749135;
CC P06850; Q9BYS1: KRTAP1-5; NbExp=3; IntAct=EBI-3870390, EBI-11741292;
CC P06850; P60410: KRTAP10-8; NbExp=3; IntAct=EBI-3870390, EBI-10171774;
CC P06850; P26371: KRTAP5-9; NbExp=3; IntAct=EBI-3870390, EBI-3958099;
CC P06850; Q9BYQ3: KRTAP9-3; NbExp=3; IntAct=EBI-3870390, EBI-1043191;
CC P06850; Q99750: MDFI; NbExp=3; IntAct=EBI-3870390, EBI-724076;
CC P06850; P0DPK4: NOTCH2NLC; NbExp=3; IntAct=EBI-3870390, EBI-22310682;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P06296}.
CC -!- TISSUE SPECIFICITY: Produced by the hypothalamus and placenta.
CC {ECO:0000269|PubMed:2783917, ECO:0000269|PubMed:3262120}.
CC -!- SIMILARITY: Belongs to the sauvagine/corticotropin-releasing
CC factor/urotensin I family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Corticotropin-releasing hormone
CC entry;
CC URL="https://en.wikipedia.org/wiki/Corticotropin-releasing_hormone";
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DR EMBL; V00571; CAA23834.1; -; Genomic_DNA.
DR EMBL; BT007453; AAP36121.1; -; mRNA.
DR EMBL; AK075431; BAG52136.1; -; mRNA.
DR EMBL; CH471068; EAW86897.1; -; Genomic_DNA.
DR EMBL; BC002599; AAH02599.1; -; mRNA.
DR EMBL; BC011031; AAH11031.1; -; mRNA.
DR CCDS; CCDS6188.1; -.
DR PIR; A30327; A30327.
DR RefSeq; NP_000747.1; NM_000756.3.
DR RefSeq; XP_016868579.1; XM_017013090.1.
DR RefSeq; XP_016868580.1; XM_017013091.1.
DR RefSeq; XP_016868581.1; XM_017013092.1.
DR RefSeq; XP_016868582.1; XM_017013093.1.
DR PDB; 1GO9; NMR; -; A=154-194.
DR PDB; 1GOE; NMR; -; A=154-194.
DR PDB; 3EHT; X-ray; 3.40 A; B=180-194.
DR PDB; 3EHU; X-ray; 1.96 A; C/D=175-194.
DR PDB; 6P9X; EM; 2.91 A; P=154-194.
DR PDBsum; 1GO9; -.
DR PDBsum; 1GOE; -.
DR PDBsum; 3EHT; -.
DR PDBsum; 3EHU; -.
DR PDBsum; 6P9X; -.
DR AlphaFoldDB; P06850; -.
DR SMR; P06850; -.
DR BioGRID; 107782; 22.
DR IntAct; P06850; 18.
DR STRING; 9606.ENSP00000276571; -.
DR DrugBank; DB02952; 2-aminoisobutyric acid.
DR DrugBank; DB01285; Corticotropin.
DR DrugBank; DB02556; D-Phenylalanine.
DR iPTMnet; P06850; -.
DR PhosphoSitePlus; P06850; -.
DR BioMuta; CRH; -.
DR DMDM; 117445; -.
DR MassIVE; P06850; -.
DR PaxDb; P06850; -.
DR PeptideAtlas; P06850; -.
DR PRIDE; P06850; -.
DR ProteomicsDB; 51935; -.
DR TopDownProteomics; P06850; -.
DR Antibodypedia; 11984; 555 antibodies from 39 providers.
DR DNASU; 1392; -.
DR Ensembl; ENST00000276571.5; ENSP00000276571.3; ENSG00000147571.5.
DR GeneID; 1392; -.
DR KEGG; hsa:1392; -.
DR MANE-Select; ENST00000276571.5; ENSP00000276571.3; NM_000756.4; NP_000747.1.
DR UCSC; uc003xvy.3; human.
DR CTD; 1392; -.
DR DisGeNET; 1392; -.
DR GeneCards; CRH; -.
DR GeneReviews; CRH; -.
DR HGNC; HGNC:2355; CRH.
DR HPA; ENSG00000147571; Tissue enriched (brain).
DR MalaCards; CRH; -.
DR MIM; 122560; gene+phenotype.
DR neXtProt; NX_P06850; -.
DR OpenTargets; ENSG00000147571; -.
DR Orphanet; 98784; Autosomal dominant nocturnal frontal lobe epilepsy.
DR PharmGKB; PA119; -.
DR VEuPathDB; HostDB:ENSG00000147571; -.
DR eggNOG; ENOG502S25G; Eukaryota.
DR GeneTree; ENSGT00940000154473; -.
DR HOGENOM; CLU_136288_0_0_1; -.
DR InParanoid; P06850; -.
DR OMA; HNNRKLM; -.
DR OrthoDB; 1532326at2759; -.
DR PhylomeDB; P06850; -.
DR TreeFam; TF332956; -.
DR PathwayCommons; P06850; -.
DR Reactome; R-HSA-373080; Class B/2 (Secretin family receptors).
DR Reactome; R-HSA-418555; G alpha (s) signalling events.
DR Reactome; R-HSA-9022702; MECP2 regulates transcription of neuronal ligands.
DR Reactome; R-HSA-9660821; ADORA2B mediated anti-inflammatory cytokines production.
DR SignaLink; P06850; -.
DR SIGNOR; P06850; -.
DR BioGRID-ORCS; 1392; 19 hits in 1070 CRISPR screens.
DR EvolutionaryTrace; P06850; -.
DR GeneWiki; Corticotropin-releasing_hormone; -.
DR GenomeRNAi; 1392; -.
DR Pharos; P06850; Tbio.
DR PRO; PR:P06850; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; P06850; protein.
DR Bgee; ENSG00000147571; Expressed in lateral nuclear group of thalamus and 74 other tissues.
DR ExpressionAtlas; P06850; baseline and differential.
DR Genevisible; P06850; HS.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0045202; C:synapse; IEA:GOC.
DR GO; GO:0017045; F:corticotropin-releasing hormone activity; IBA:GO_Central.
DR GO; GO:0005179; F:hormone activity; TAS:ProtInc.
DR GO; GO:0005184; F:neuropeptide hormone activity; TAS:ProtInc.
DR GO; GO:0005102; F:signaling receptor binding; TAS:ProtInc.
DR GO; GO:0030325; P:adrenal gland development; IEA:Ensembl.
DR GO; GO:0007268; P:chemical synaptic transmission; TAS:ProtInc.
DR GO; GO:0007565; P:female pregnancy; IDA:UniProtKB.
DR GO; GO:0006704; P:glucocorticoid biosynthetic process; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IDA:UniProtKB.
DR GO; GO:0007611; P:learning or memory; TAS:ProtInc.
DR GO; GO:0035641; P:locomotory exploration behavior; IEA:Ensembl.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0042322; P:negative regulation of circadian sleep/wake cycle, REM sleep; NAS:BHF-UCL.
DR GO; GO:0032811; P:negative regulation of epinephrine secretion; IBA:GO_Central.
DR GO; GO:0070093; P:negative regulation of glucagon secretion; IBA:GO_Central.
DR GO; GO:0007567; P:parturition; TAS:ProtInc.
DR GO; GO:0010841; P:positive regulation of circadian sleep/wake cycle, wakefulness; NAS:BHF-UCL.
DR GO; GO:0051461; P:positive regulation of corticotropin secretion; IDA:UniProtKB.
DR GO; GO:0051464; P:positive regulation of cortisol secretion; IDA:BHF-UCL.
DR GO; GO:2000310; P:regulation of NMDA receptor activity; IDA:UniProtKB.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR GO; GO:0001963; P:synaptic transmission, dopaminergic; IDA:UniProtKB.
DR InterPro; IPR018446; Corticotropin-releasing_fac_CS.
DR InterPro; IPR000187; CRF.
DR InterPro; IPR003620; Urocortin_CRF.
DR PANTHER; PTHR15035; PTHR15035; 1.
DR Pfam; PF00473; CRF; 1.
DR PRINTS; PR01612; CRFFAMILY.
DR SMART; SM00039; CRF; 1.
DR PROSITE; PS00511; CRF; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amidation; Cleavage on pair of basic residues;
KW Direct protein sequencing; Hormone; Reference proteome; Secreted; Signal.
FT SIGNAL 1..24
FT /evidence="ECO:0000305"
FT PROPEP 25..153
FT /evidence="ECO:0000269|PubMed:3262120"
FT /id="PRO_0000006212"
FT PEPTIDE 154..194
FT /note="Corticoliberin"
FT /id="PRO_0000006213"
FT REGION 32..61
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 85..105
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 136..158
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 43..57
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 144..158
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 194
FT /note="Isoleucine amide"
FT /evidence="ECO:0000269|PubMed:6605851"
FT VARIANT 30
FT /note="P -> R (found in patients with autosomal dominant
FT nocturnal frontal lobe epilepsy; unknown pathological
FT significance; results in decreased protein levels;
FT decreased protein secretion; dbSNP:rs748404250)"
FT /evidence="ECO:0000269|PubMed:23593457"
FT /id="VAR_075504"
FT MUTAGEN 183
FT /note="Q->A: Strongly reduced affinity for CRFR1."
FT /evidence="ECO:0000269|PubMed:18801728"
FT MUTAGEN 187
FT /note="N->A: No effect on affinity for CRFR1."
FT /evidence="ECO:0000269|PubMed:18801728"
FT MUTAGEN 188
FT /note="R->A: Strongly reduced affinity for CRFR1."
FT /evidence="ECO:0000269|PubMed:18801728"
FT MUTAGEN 190
FT /note="L->A: Strongly reduced affinity for CRFR1."
FT /evidence="ECO:0000269|PubMed:18801728"
FT MUTAGEN 191
FT /note="M->A: Strongly reduced affinity for CRFR1."
FT /evidence="ECO:0000269|PubMed:18801728"
FT MUTAGEN 192
FT /note="E->A: No effect on affinity for CRFR1."
FT /evidence="ECO:0000269|PubMed:18801728"
FT HELIX 160..162
FT /evidence="ECO:0007829|PDB:6P9X"
FT HELIX 180..193
FT /evidence="ECO:0007829|PDB:3EHU"
SQ SEQUENCE 196 AA; 21422 MW; 0CCDFF05BE364E92 CRC64;
MRLPLLVSAG VLLVALLPCP PCRALLSRGP VPGARQAPQH PQPLDFFQPP PQSEQPQQPQ
ARPVLLRMGE EYFLRLGNLN KSPAAPLSPA SSLLAGGSGS RPSPEQATAN FFRVLLQQLL
LPRRSLDSPA ALAERGARNA LGGHQEAPER ERRSEEPPIS LDLTFHLLRE VLEMARAEQL
AQQAHSNRKL MEIIGK
