ID CRLF1_HUMAN Reviewed; 422 AA. AC O75462; Q9UHH5; DT 01-MAR-2004, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1998, sequence version 1. DT 13-FEB-2019, entry version 168. DE RecName: Full=Cytokine receptor-like factor 1; DE AltName: Full=Cytokine-like factor 1; DE Short=CLF-1; DE AltName: Full=ZcytoR5; DE Flags: Precursor; GN Name=CRLF1; ORFNames=UNQ288/PRO327; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], SUBUNIT, SUBCELLULAR LOCATION, TISSUE RP SPECIFICITY, AND INDUCTION. RC TISSUE=Fetal lung; RX PubMed=9686600; RA Elson G.C.A., Graber P., Losberger C., Herren S., Gretener D., RA Menoud L.N., Wells T.N.C., Kosco-Vilbois M.H., Gauchat J.-F.; RT "Cytokine-like factor-1, a novel soluble protein, shares homology with RT members of the cytokine type I receptor family."; RL J. Immunol. 161:1371-1379(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Magrangeas F., Jacques Y., Minvielle S.; RT "Cloning and expression of a novel soluble protein containing RT hematopoietic cytokine receptor domains."; RL Submitted (JUN-1998) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Lok S., Presnell S.R., Jelmberg A.C., Gilbert T., Whitmore T.E., RA Foster D.C., Adams R.L., Lehner J.M., O'Hara P.J.; RL Submitted (AUG-1999) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=12975309; DOI=10.1101/gr.1293003; RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., RA Wood W.I., Godowski P.J., Gray A.M.; RT "The secreted protein discovery initiative (SPDI), a large-scale RT effort to identify novel human secreted and transmembrane proteins: a RT bioinformatics assessment."; RL Genome Res. 13:2265-2270(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lymph; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP PROTEIN SEQUENCE OF 38-52. RX PubMed=15340161; DOI=10.1110/ps.04682504; RA Zhang Z., Henzel W.J.; RT "Signal peptide prediction based on analysis of experimentally RT verified cleavage sites."; RL Protein Sci. 13:2819-2824(2004). RN [7] RP INTERACTION WITH CLC AND CNTFR. RX PubMed=10966616; DOI=10.1038/78765; RA Elson G.C.A., Lelievre E., Guillet C., Chevalier S., Plun-Favreau H., RA Froger J., Suard I., de Coignac A.B., Delneste Y., Bonnefoy J.-Y., RA Gauchat J.-F., Gascan H.; RT "CLF associates with CLC to form a functional heteromeric ligand for RT the CNTF receptor complex."; RL Nat. Neurosci. 3:867-872(2000). RN [8] RP VARIANTS CISS1 HIS-81 AND ARG-374. RX PubMed=12509788; DOI=10.1086/346120; RA Knappskog P.M., Majewski J., Livneh A., Nilsen P.T.E., Bringsli J.S., RA Ott J., Boman H.; RT "Cold-induced sweating syndrome is caused by mutations in the CRLF1 RT gene."; RL Am. J. Hum. Genet. 72:375-383(2003). RN [9] RP VARIANT CISS1 CYS-284. RX PubMed=16952376; DOI=10.1016/j.jns.2006.07.001; RA Hahn A.F., Jones D.L., Knappskog P.M., Boman H., McLeod J.G.; RT "Cold-induced sweating syndrome: a report of two cases and RT demonstration of genetic heterogeneity."; RL J. Neurol. Sci. 250:62-70(2006). RN [10] RP VARIANT CISS1 GLY-76. RX PubMed=17436251; DOI=10.1086/513608; RA Dagoneau N., Bellais S., Blanchet P., Sarda P., Al-Gazali L.I., RA Di Rocco M., Huber C., Djouadi F., Le Goff C., Munnich A., RA Cormier-Daire V.; RT "Mutations in cytokine receptor-like factor 1 (CRLF1) account for both RT Crisponi and cold-induced sweating syndromes."; RL Am. J. Hum. Genet. 80:966-970(2007). RN [11] RP VARIANT CISS1 GLY-76. RX PubMed=17436252; DOI=10.1086/516843; RA Crisponi L., Crisponi G., Meloni A., Toliat M.R., Nurnberg G., RA Usala G., Uda M., Masala M., Hohne W., Becker C., Marongiu M., RA Chiappe F., Kleta R., Rauch A., Wollnik B., Strasser F., Reese T., RA Jakobs C., Kurlemann G., Cao A., Nurnberg P., Rutsch F.; RT "Crisponi syndrome is caused by mutations in the CRLF1 gene and is RT allelic to cold-induced sweating syndrome type 1."; RL Am. J. Hum. Genet. 80:971-981(2007). RN [12] RP VARIANTS CISS1 ASP-75; ILE-113 AND PRO-114. RX PubMed=21326283; DOI=10.1038/ejhg.2010.253; RA Herholz J., Meloni A., Marongiu M., Chiappe F., Deiana M., RA Herrero C.R., Zampino G., Hamamy H., Zalloum Y., Waaler P.E., RA Crisponi G., Crisponi L., Rutsch F.; RT "Differential secretion of the mutated protein is a major component RT affecting phenotypic severity in CRLF1-associated disorders."; RL Eur. J. Hum. Genet. 19:525-533(2011). RN [13] RP VARIANT CISS1 LEU-138. RX PubMed=23026229; DOI=10.1016/j.braindev.2012.08.011; RA Tuysuz B., Kasapcopur O., Yalcinkaya C., Isik Hasiloglu Z., RA Knappskog P.M., Boman H.; RT "Multiple small hyperintense lesions in the subcortical white matter RT on cranial MR images in two Turkish brothers with cold-induced RT sweating syndrome caused by a novel missense mutation in the CRLF1 RT gene."; RL Brain Dev. 35:596-601(2013). RN [14] RP VARIANTS CISS1 PRO-74; PRO-145; CYS-216; SER-268; PRO-312 AND CYS-340. RX PubMed=24488861; DOI=10.1002/humu.22522; RA Piras R., Chiappe F., Torraca I.L., Buers I., Usala G., Angius A., RA Akin M.A., Basel-Vanagaite L., Benedicenti F., Chiodin E., El Assy O., RA Feingold-Zadok M., Guibert J., Kamien B., Kasapkara C.S., Kilic E., RA Boduroglu K., Kurtoglu S., Manzur A.Y., Onal E.E., Paderi E., RA Roche C.H., Tumer L., Unal S., Utine G.E., Zanda G., Zankl A., RA Zampino G., Crisponi G., Crisponi L., Rutsch F.; RT "Expanding the mutational spectrum of CRLF1 in Crisponi/CISS1 RT syndrome."; RL Hum. Mutat. 35:424-433(2014). CC -!- FUNCTION: Cytokine receptor subunit, possibly playing a regulatory CC role in the immune system and during fetal development. May be CC involved in nervous system development. CC -!- SUBUNIT: Forms covalently linked di- and tetramers. Forms a CC heteromeric complex with cardiotrophin-like cytokine (CLC); the CC CRLF1/CLC complex is a ligand for the ciliary neurotrophic factor CC receptor (CNTFR). {ECO:0000269|PubMed:9686600}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:9686600}. CC -!- TISSUE SPECIFICITY: Highest levels of expression observed in CC spleen, thymus, lymph node, appendix, bone marrow, stomach, CC placenta, heart, thyroid and ovary. Strongly expressed also in CC fetal lung. {ECO:0000269|PubMed:9686600}. CC -!- INDUCTION: Up-regulated in fibroblast primary cell cultures under CC stimulation by IFNG/IFN-gamma, TNF and IL6/interleukin-6. CC {ECO:0000269|PubMed:9686600}. CC -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein CC folding and thereby efficient intracellular transport and cell- CC surface receptor binding. CC -!- DISEASE: Crisponi/Cold-induced sweating syndrome 1 (CISS1) CC [MIM:272430]: An autosomal recessive disorder characterized by CC profuse sweating induced by cool surroundings (temperatures of 7 CC to 18 degrees Celsius). Patients manifest, in the neonatal period, CC orofacial weakness with impaired sucking and swallowing, resulting CC in poor feeding. Affected infants show a tendency to startle, with CC contractions of the facial muscles in response to tactile stimuli CC or during crying, trismus, abundant salivation, and opisthotonus. CC These features are referred to as Crisponi syndrome and can result CC in early death in infancy. Patients who survive into childhood CC have hyperhidrosis, mainly of the upper body, in response to cold CC temperatures, and sweat very little with heat. Additional CC abnormalities include a high-arched palate, nasal voice, depressed CC nasal bridge, inability to fully extend the elbows and CC kyphoscoliosis. {ECO:0000269|PubMed:12509788, CC ECO:0000269|PubMed:16952376, ECO:0000269|PubMed:17436251, CC ECO:0000269|PubMed:17436252, ECO:0000269|PubMed:21326283, CC ECO:0000269|PubMed:23026229, ECO:0000269|PubMed:24488861}. CC Note=The disease is caused by mutations affecting the gene CC represented in this entry. CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 3 CC subfamily. {ECO:0000305}. 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; AF059293; AAC28335.1; -; mRNA. DR EMBL; AF073515; AAD39681.1; -; mRNA. DR EMBL; AF178684; AAD54385.1; -; mRNA. DR EMBL; AY358291; AAQ88658.1; -; mRNA. DR EMBL; BC044634; AAH44634.1; -; mRNA. DR CCDS; CCDS32962.1; -. DR RefSeq; NP_004741.1; NM_004750.4. DR UniGene; Hs.114948; -. DR ProteinModelPortal; O75462; -. DR SMR; O75462; -. DR BioGrid; 114670; 5. DR DIP; DIP-61205N; -. DR IntAct; O75462; 1. DR STRING; 9606.ENSP00000376188; -. DR GlyConnect; 1167; -. DR iPTMnet; O75462; -. DR PhosphoSitePlus; O75462; -. DR BioMuta; CRLF1; -. DR EPD; O75462; -. DR jPOST; O75462; -. DR MaxQB; O75462; -. DR PaxDb; O75462; -. DR PeptideAtlas; O75462; -. DR PRIDE; O75462; -. DR ProteomicsDB; 50025; -. DR DNASU; 9244; -. DR Ensembl; ENST00000392386; ENSP00000376188; ENSG00000006016. DR GeneID; 9244; -. DR KEGG; hsa:9244; -. DR UCSC; uc010ebt.3; human. DR CTD; 9244; -. DR DisGeNET; 9244; -. DR EuPathDB; HostDB:ENSG00000006016.10; -. DR GeneCards; CRLF1; -. DR GeneReviews; CRLF1; -. DR HGNC; HGNC:2364; CRLF1. DR HPA; HPA041493; -. DR HPA; HPA041793; -. DR MalaCards; CRLF1; -. DR MIM; 272430; phenotype. DR MIM; 604237; gene. DR neXtProt; NX_O75462; -. DR OpenTargets; ENSG00000006016; -. DR Orphanet; 157820; Cold-induced sweating syndrome. DR Orphanet; 1545; Crisponi syndrome. DR Orphanet; 930; Idiopathic achalasia. DR PharmGKB; PA26882; -. DR eggNOG; ENOG410IV7Y; Eukaryota. DR eggNOG; ENOG410Z87J; LUCA. DR GeneTree; ENSGT00940000156569; -. DR HOGENOM; HOG000111972; -. DR HOVERGEN; HBG051119; -. DR InParanoid; O75462; -. DR OMA; HKTRNQA; -. DR OrthoDB; 702827at2759; -. DR PhylomeDB; O75462; -. DR TreeFam; TF106501; -. DR BRENDA; 1.1.1.105; 2681. DR Reactome; R-HSA-6788467; IL-6-type cytokine receptor ligand interactions. DR Reactome; R-HSA-9020956; Interleukin-27 signaling. DR SignaLink; O75462; -. DR SIGNOR; O75462; -. DR GeneWiki; CRLF1; -. DR GenomeRNAi; 9244; -. DR PRO; PR:O75462; -. DR Proteomes; UP000005640; Chromosome 19. DR Bgee; ENSG00000006016; Expressed in 172 organ(s), highest expression level in right coronary artery. DR ExpressionAtlas; O75462; baseline and differential. DR Genevisible; O75462; HS. DR GO; GO:0097058; C:CRLF-CLCF1 complex; IDA:BHF-UCL. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; TAS:ProtInc. DR GO; GO:0043235; C:receptor complex; IBA:GO_Central. DR GO; GO:0019955; F:cytokine binding; IPI:HGNC. DR GO; GO:0004896; F:cytokine receptor activity; IBA:GO_Central. DR GO; GO:0046982; F:protein heterodimerization activity; IDA:BHF-UCL. DR GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome. DR GO; GO:0070106; P:interleukin-27-mediated signaling pathway; TAS:Reactome. DR GO; GO:2000672; P:negative regulation of motor neuron apoptotic process; IEA:Ensembl. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:BHF-UCL. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:BHF-UCL. DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; IDA:BHF-UCL. DR GO; GO:0010469; P:regulation of signaling receptor activity; IEA:GOC. DR GO; GO:0001657; P:ureteric bud development; IEA:Ensembl. DR CDD; cd00063; FN3; 2. DR Gene3D; 2.60.40.10; -; 3. DR InterPro; IPR003961; FN3_dom. DR InterPro; IPR036116; FN3_sf. DR InterPro; IPR015152; Growth/epo_recpt_lig-bind. DR InterPro; IPR036179; Ig-like_dom_sf. DR InterPro; IPR013783; Ig-like_fold. DR Pfam; PF09067; EpoR_lig-bind; 1. DR Pfam; PF00041; fn3; 1. DR SMART; SM00060; FN3; 2. DR SUPFAM; SSF48726; SSF48726; 1. DR SUPFAM; SSF49265; SSF49265; 2. DR PROSITE; PS50853; FN3; 2. PE 1: Evidence at protein level; KW Complete proteome; Direct protein sequencing; Disease mutation; KW Disulfide bond; Glycoprotein; Immunoglobulin domain; Phosphoprotein; KW Polymorphism; Receptor; Reference proteome; Repeat; Secreted; Signal. FT SIGNAL 1 37 {ECO:0000269|PubMed:15340161}. FT CHAIN 38 422 Cytokine receptor-like factor 1. FT /FTId=PRO_0000011039. FT DOMAIN 38 131 Ig-like C2-type. FT DOMAIN 137 232 Fibronectin type-III 1. FT {ECO:0000255|PROSITE-ProRule:PRU00316}. FT DOMAIN 237 341 Fibronectin type-III 2. FT {ECO:0000255|PROSITE-ProRule:PRU00316}. FT MOTIF 327 331 WSXWS motif. FT MOD_RES 219 219 Phosphoserine. FT {ECO:0000250|UniProtKB:Q9JM58}. FT CARBOHYD 92 92 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 104 104 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 140 140 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 168 168 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 292 292 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 382 382 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT DISULFID 143 153 {ECO:0000250}. FT DISULFID 184 195 {ECO:0000250}. FT VARIANT 74 74 L -> P (in CISS1; dbSNP:rs1295488778). FT {ECO:0000269|PubMed:24488861}. FT /FTId=VAR_070817. FT VARIANT 75 75 Y -> D (in CISS1). FT {ECO:0000269|PubMed:21326283}. FT /FTId=VAR_070818. FT VARIANT 76 76 W -> G (in CISS1; dbSNP:rs137853143). FT {ECO:0000269|PubMed:17436251, FT ECO:0000269|PubMed:17436252}. FT /FTId=VAR_033113. FT VARIANT 81 81 R -> H (in CISS1; dbSNP:rs104894670). FT {ECO:0000269|PubMed:12509788}. FT /FTId=VAR_017865. FT VARIANT 113 113 N -> I (in CISS1; together with P-114). FT {ECO:0000269|PubMed:21326283}. FT /FTId=VAR_070819. FT VARIANT 114 114 L -> P (in CISS1; together with I-113; FT dbSNP:rs774359694). FT {ECO:0000269|PubMed:21326283}. FT /FTId=VAR_070820. FT VARIANT 138 138 P -> L (in CISS1; dbSNP:rs137853930). FT {ECO:0000269|PubMed:23026229}. FT /FTId=VAR_070821. FT VARIANT 145 145 S -> P (in CISS1). FT {ECO:0000269|PubMed:24488861}. FT /FTId=VAR_070822. FT VARIANT 176 176 R -> K (in dbSNP:rs11672248). FT /FTId=VAR_028355. FT VARIANT 216 216 R -> C (in CISS1; dbSNP:rs556029569). FT {ECO:0000269|PubMed:24488861}. FT /FTId=VAR_070823. FT VARIANT 268 268 F -> S (in CISS1; dbSNP:rs761982168). FT {ECO:0000269|PubMed:24488861}. FT /FTId=VAR_070824. FT VARIANT 284 284 W -> C (in CISS1; dbSNP:rs137853927). FT {ECO:0000269|PubMed:16952376}. FT /FTId=VAR_070825. FT VARIANT 312 312 R -> P (in CISS1; dbSNP:rs137853933). FT {ECO:0000269|PubMed:24488861}. FT /FTId=VAR_070826. FT VARIANT 340 340 R -> C (in CISS1; dbSNP:rs771459625). FT {ECO:0000269|PubMed:24488861}. FT /FTId=VAR_070827. FT VARIANT 374 374 L -> R (in CISS1; dbSNP:rs104894668). FT {ECO:0000269|PubMed:12509788}. FT /FTId=VAR_017866. FT CONFLICT 240 240 D -> E (in Ref. 3; AAD54385). FT {ECO:0000305}. SQ SEQUENCE 422 AA; 46302 MW; AD9DEFCB01B84228 CRC64; MPAGRRGPAA QSARRPPPLL PLLLLLCVLG APRAGSGAHT AVISPQDPTL LIGSSLLATC SVHGDPPGAT AEGLYWTLNG RRLPPELSRV LNASTLALAL ANLNGSRQRS GDNLVCHARD GSILAGSCLY VGLPPEKPVN ISCWSKNMKD LTCRWTPGAH GETFLHTNYS LKYKLRWYGQ DNTCEEYHTV GPHSCHIPKD LALFTPYEIW VEATNRLGSA RSDVLTLDIL DVVTTDPPPD VHVSRVGGLE DQLSVRWVSP PALKDFLFQA KYQIRYRVED SVDWKVVDDV SNQTSCRLAG LKPGTVYFVQ VRCNPFGIYG SKKAGIWSEW SHPTAASTPR SERPGPGGGA CEPRGGEPSS GPVRRELKQF LGWLKKHAYC SNLSFRLYDQ WRAWMQKSHK TRNQDEGILP SGRRGTARGP AR //