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 24-JAN-2024, entry version 211. 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"; 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; 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 EMDB; EMD-20277; -. 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; 9606-ENSP00000276571; -. DR PeptideAtlas; P06850; -. DR ProteomicsDB; 51935; -. DR TopDownProteomics; P06850; -. DR Antibodypedia; 11984; 629 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 AGR; HGNC:2355; -. 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; 4266825at2759; -. 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 SignaLink; P06850; -. DR SIGNOR; P06850; -. DR BioGRID-ORCS; 1392; 21 hits in 1148 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 cell types or tissues. DR ExpressionAtlas; P06850; baseline and differential. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0043204; C:perikaryon; IEA:Ensembl. DR GO; GO:0045202; C:synapse; IEA:GOC. DR GO; GO:0043196; C:varicosity; IEA:Ensembl. DR GO; GO:0017045; F:corticotropin-releasing hormone activity; IBA:GO_Central. DR GO; GO:0051430; F:corticotropin-releasing hormone receptor 1 binding; IEA:Ensembl. DR GO; GO:0051431; F:corticotropin-releasing hormone receptor 2 binding; IEA:Ensembl. 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:0008306; P:associative learning; IEA:Ensembl. DR GO; GO:0071314; P:cellular response to cocaine; IEA:Ensembl. DR GO; GO:0071549; P:cellular response to dexamethasone stimulus; IEA:Ensembl. DR GO; GO:0007268; P:chemical synaptic transmission; TAS:ProtInc. DR GO; GO:0016101; P:diterpenoid metabolic process; IEA:Ensembl. DR GO; GO:0007565; P:female pregnancy; IDA:UniProtKB. DR GO; GO:0006704; P:glucocorticoid biosynthetic process; IEA:Ensembl. DR GO; GO:0008628; P:hormone-mediated apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0021854; P:hypothalamus development; 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:0060291; P:long-term synaptic potentiation; IEA:Ensembl. DR GO; GO:0030324; P:lung development; IEA:Ensembl. DR GO; GO:0050801; P:monoatomic ion homeostasis; 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:0010629; P:negative regulation of gene expression; IEA:Ensembl. DR GO; GO:0070093; P:negative regulation of glucagon secretion; IBA:GO_Central. DR GO; GO:0033685; P:negative regulation of luteinizing hormone secretion; IEA:Ensembl. DR GO; GO:0010700; P:negative regulation of norepinephrine secretion; IEA:Ensembl. DR GO; GO:0003085; P:negative regulation of systemic arterial blood pressure; IEA:Ensembl. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0007567; P:parturition; TAS:ProtInc. DR GO; GO:2000987; P:positive regulation of behavioral fear response; IEA:Ensembl. DR GO; GO:0090280; P:positive regulation of calcium ion import; IEA:Ensembl. DR GO; GO:0043950; P:positive regulation of cAMP-mediated signaling; IEA:Ensembl. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IEA:Ensembl. DR GO; GO:0010841; P:positive regulation of circadian sleep/wake cycle, wakefulness; NAS:BHF-UCL. DR GO; GO:2000854; P:positive regulation of corticosterone secretion; IEA:Ensembl. 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:0060456; P:positive regulation of digestive system process; IEA:Ensembl. DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl. DR GO; GO:0035774; P:positive regulation of insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IEA:Ensembl. DR GO; GO:2000310; P:regulation of NMDA receptor activity; IDA:UniProtKB. DR GO; GO:0014062; P:regulation of serotonin secretion; IEA:Ensembl. DR GO; GO:1904044; P:response to aldosterone; IEA:Ensembl. DR GO; GO:0051412; P:response to corticosterone; IEA:Ensembl. DR GO; GO:0043627; P:response to estrogen; IEA:Ensembl. DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl. DR GO; GO:0045472; P:response to ether; IEA:Ensembl. DR GO; GO:0035902; P:response to immobilization stress; IEA:Ensembl. DR GO; GO:0048265; P:response to pain; IEA:Ensembl. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0001963; P:synaptic transmission, dopaminergic; IDA:UniProtKB. DR Gene3D; 6.10.250.1920; -; 1. DR InterPro; IPR018446; Corticotropin-releasing_fac_CS. DR InterPro; IPR000187; CRF. DR InterPro; IPR003620; Urocortin_CRF. DR PANTHER; PTHR15035:SF9; CORTICOLIBERIN; 1. DR PANTHER; PTHR15035; CORTICOLIBERIN/UROCORTIN; 1. DR Pfam; PF00473; CRF; 1. DR PRINTS; PR01612; CRFFAMILY. DR SMART; SM00039; CRF; 1. DR PROSITE; PS00511; CRF; 1. DR Genevisible; P06850; HS. 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; uncertain significance; FT results in decreased protein levels; decreased protein FT 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 //