ID KLOTB_MOUSE Reviewed; 1043 AA.
AC Q99N32; B2RQN8; Q920J2; Q99N31;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 24-JAN-2024, entry version 154.
DE RecName: Full=Beta-klotho;
DE Short=BKL;
DE Short=BetaKlotho;
DE AltName: Full=Klotho beta-like protein;
GN Name=Klb; Synonyms=Betakl;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY, AND
RP DEVELOPMENTAL STAGE.
RC STRAIN=Swiss Webster; TISSUE=Liver;
RX PubMed=11044614; DOI=10.1016/s0925-4773(00)00439-1;
RA Ito S., Kinoshita S., Shiraishi N., Nakagawa S., Sekine S., Fujimori T.,
RA Nabeshima Y.;
RT "Molecular cloning and expression analyses of mouse betaklotho, which
RT encodes a novel Klotho family protein.";
RL Mech. Dev. 98:115-119(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [3]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=16075061; DOI=10.1172/jci23076;
RA Ito S., Fujimori T., Furuya A., Satoh J., Nabeshima Y., Nabeshima Y.;
RT "Impaired negative feedback suppression of bile acid synthesis in mice
RT lacking betaKlotho.";
RL J. Clin. Invest. 115:2202-2208(2005).
RN [4]
RP FUNCTION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND INTERACTION WITH
RP FGFR1 AND FGFR4.
RX PubMed=17452648; DOI=10.1073/pnas.0701600104;
RA Ogawa Y., Kurosu H., Yamamoto M., Nandi A., Rosenblatt K.P., Goetz R.,
RA Eliseenkova A.V., Mohammadi M., Kuro-o M.;
RT "BetaKlotho is required for metabolic activity of fibroblast growth factor
RT 21.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:7432-7437(2007).
CC -!- FUNCTION: Contributes to the transcriptional repression of cholesterol
CC 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid
CC synthesis. Probably inactive as a glycosidase. Increases the ability of
CC FGFR1 and FGFR4 to bind FGF21. {ECO:0000269|PubMed:16075061,
CC ECO:0000269|PubMed:17452648}.
CC -!- SUBUNIT: Interacts with FGF19; this interaction is direct. Interacts
CC (via C-terminus) with FGF21; this interaction is direct (By
CC similarity). Interacts with FGFR1 and FGFR4. {ECO:0000250,
CC ECO:0000269|PubMed:17452648}.
CC -!- INTERACTION:
CC Q99N32; P16092: Fgfr1; NbExp=3; IntAct=EBI-15633521, EBI-7953898;
CC Q99N32; Q03142: Fgfr4; NbExp=2; IntAct=EBI-15633521, EBI-15633599;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000305}; Single-pass type III
CC membrane protein {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q99N32-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q99N32-2; Sequence=VSP_015830, VSP_015831;
CC -!- TISSUE SPECIFICITY: Present in liver, muscle and white adipose tissue,
CC but not in kidney (at protein level). Expressed in liver and pancreas,
CC and at lower levels in skin, stomach, skeletal muscle, small intestine
CC and lung. {ECO:0000269|PubMed:11044614, ECO:0000269|PubMed:16075061,
CC ECO:0000269|PubMed:17452648}.
CC -!- DEVELOPMENTAL STAGE: Expression starts at 10.5 dpc in hepatocytes.
CC Expressed in the acinar cells of the pancreas and cervical brown
CC adipose tissue at 15.5 dpc. Expressed in white adipose tissue at 19.5
CC dpc. Up-regulated during preadipocyte differentiation into adipocytes
CC (at protein level). {ECO:0000269|PubMed:11044614,
CC ECO:0000269|PubMed:17452648}.
CC -!- DOMAIN: Contains 2 glycosyl hydrolase 1 regions. However, the first
CC region lacks the essential Glu active site residue at position 241, and
CC the second one lacks the essential Glu active site residue at position
CC 887. These domains are therefore predicted to be inactive.
CC -!- DISRUPTION PHENOTYPE: Mice are viable and fertile, but have an altered
CC bile metabolism: they have increased CYP7A1 levels, secrete more bile
CC acids and are resistant to cholesterol gallstone formation.
CC {ECO:0000269|PubMed:16075061}.
CC -!- SIMILARITY: Belongs to the glycosyl hydrolase 1 family. Klotho
CC subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAL01648.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AF178429; AAL01648.1; ALT_INIT; mRNA.
DR EMBL; AF165170; AAK28704.1; -; mRNA.
DR EMBL; AF165171; AAK28705.1; -; mRNA.
DR EMBL; BC138008; AAI38009.1; -; mRNA.
DR EMBL; BC138010; AAI38011.1; -; mRNA.
DR CCDS; CCDS19306.1; -. [Q99N32-1]
DR RefSeq; NP_112457.1; NM_031180.2. [Q99N32-1]
DR AlphaFoldDB; Q99N32; -.
DR SMR; Q99N32; -.
DR BioGRID; 219908; 4.
DR DIP; DIP-60918N; -.
DR IntAct; Q99N32; 2.
DR STRING; 10090.ENSMUSP00000031096; -.
DR CAZy; GH1; Glycoside Hydrolase Family 1.
DR GlyCosmos; Q99N32; 12 sites, No reported glycans.
DR GlyGen; Q99N32; 12 sites.
DR iPTMnet; Q99N32; -.
DR PhosphoSitePlus; Q99N32; -.
DR PaxDb; 10090-ENSMUSP00000031096; -.
DR ProteomicsDB; 263663; -. [Q99N32-1]
DR ProteomicsDB; 263664; -. [Q99N32-2]
DR Antibodypedia; 10542; 233 antibodies from 22 providers.
DR DNASU; 83379; -.
DR Ensembl; ENSMUST00000031096.11; ENSMUSP00000031096.8; ENSMUSG00000029195.11. [Q99N32-1]
DR GeneID; 83379; -.
DR KEGG; mmu:83379; -.
DR UCSC; uc008xnn.1; mouse. [Q99N32-1]
DR AGR; MGI:1932466; -.
DR CTD; 152831; -.
DR MGI; MGI:1932466; Klb.
DR VEuPathDB; HostDB:ENSMUSG00000029195; -.
DR eggNOG; KOG0626; Eukaryota.
DR GeneTree; ENSGT00940000157489; -.
DR HOGENOM; CLU_001859_5_2_1; -.
DR InParanoid; Q99N32; -.
DR OMA; ARMKVTH; -.
DR OrthoDB; 3373839at2759; -.
DR PhylomeDB; Q99N32; -.
DR TreeFam; TF314803; -.
DR Reactome; R-MMU-109704; PI3K Cascade.
DR Reactome; R-MMU-1257604; PIP3 activates AKT signaling.
DR Reactome; R-MMU-1307965; betaKlotho-mediated ligand binding.
DR Reactome; R-MMU-5654228; Phospholipase C-mediated cascade, FGFR4.
DR Reactome; R-MMU-5654712; FRS-mediated FGFR4 signaling.
DR Reactome; R-MMU-5654719; SHC-mediated cascade:FGFR4.
DR Reactome; R-MMU-5654720; PI-3K cascade:FGFR4.
DR Reactome; R-MMU-5654733; Negative regulation of FGFR4 signaling.
DR Reactome; R-MMU-5673001; RAF/MAP kinase cascade.
DR Reactome; R-MMU-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR BioGRID-ORCS; 83379; 6 hits in 76 CRISPR screens.
DR ChiTaRS; Klb; mouse.
DR PRO; PR:Q99N32; -.
DR Proteomes; UP000000589; Chromosome 5.
DR RNAct; Q99N32; Protein.
DR Bgee; ENSMUSG00000029195; Expressed in brown adipose tissue and 66 other cell types or tissues.
DR ExpressionAtlas; Q99N32; baseline and differential.
DR Genevisible; Q99N32; MM.
DR GO; GO:0016020; C:membrane; ISS:MGI.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0017134; F:fibroblast growth factor binding; ISO:MGI.
DR GO; GO:0005104; F:fibroblast growth factor receptor binding; ISO:MGI.
DR GO; GO:0004553; F:hydrolase activity, hydrolyzing O-glycosyl compounds; IEA:InterPro.
DR GO; GO:0005975; P:carbohydrate metabolic process; IEA:InterPro.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; IGI:MGI.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IGI:MGI.
DR GO; GO:0090080; P:positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway; IGI:MGI.
DR Gene3D; 3.20.20.80; Glycosidases; 2.
DR InterPro; IPR001360; Glyco_hydro_1.
DR InterPro; IPR033132; Glyco_hydro_1_N_CS.
DR InterPro; IPR017853; Glycoside_hydrolase_SF.
DR PANTHER; PTHR10353:SF68; BETA-KLOTHO; 1.
DR PANTHER; PTHR10353; GLYCOSYL HYDROLASE; 1.
DR Pfam; PF00232; Glyco_hydro_1; 2.
DR PRINTS; PR00131; GLHYDRLASE1.
DR SUPFAM; SSF51445; (Trans)glycosidases; 2.
DR PROSITE; PS00653; GLYCOSYL_HYDROL_F1_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Glycoprotein; Membrane;
KW Reference proteome; Repeat; Transmembrane; Transmembrane helix.
FT CHAIN 1..1043
FT /note="Beta-klotho"
FT /id="PRO_0000063906"
FT TOPO_DOM 1..994
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 995..1015
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1016..1043
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 77..506
FT /note="Glycosyl hydrolase-1 1"
FT REGION 515..965
FT /note="Glycosyl hydrolase-1 2"
FT CARBOHYD 84
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 122
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 161
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 211
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 262
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 308
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 389
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 552
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 609
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 700
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 704
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 837
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 276..295
FT /note="AHSKVWHNYDKNFRPHQKGW -> VLYSWLLTRASELGGGVLGG (in
FT isoform 2)"
FT /evidence="ECO:0000303|PubMed:11044614"
FT /id="VSP_015830"
FT VAR_SEQ 296..1043
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11044614"
FT /id="VSP_015831"
SQ SEQUENCE 1043 AA; 120189 MW; 4CBE6735F4112D5E CRC64;
MKTGCAAGSP GNEWIFFSSD ERNTRSRKTM SNRALQRSAV LSAFVLLRAV TGFSGDGKAI
WDKKQYVSPV NPSQLFLYDT FPKNFSWGVG TGAFQVEGSW KTDGRGPSIW DRYVYSHLRG
VNGTDRSTDS YIFLEKDLLA LDFLGVSFYQ FSISWPRLFP NGTVAAVNAQ GLRYYRALLD
SLVLRNIEPI VTLYHWDLPL TLQEEYGGWK NATMIDLFND YATYCFQTFG DRVKYWITIH
NPYLVAWHGF GTGMHAPGEK GNLTAVYTVG HNLIKAHSKV WHNYDKNFRP HQKGWLSITL
GSHWIEPNRT DNMEDVINCQ HSMSSVLGWF ANPIHGDGDY PEFMKTGAMI PEFSEAEKEE
VRGTADFFAF SFGPNNFRPS NTVVKMGQNV SLNLRQVLNW IKLEYDDPQI LISENGWFTD
SYIKTEDTTA IYMMKNFLNQ VLQAIKFDEI RVFGYTAWTL LDGFEWQDAY TTRRGLFYVD
FNSEQKERKP KSSAHYYKQI IQDNGFPLKE STPDMKGRFP CDFSWGVTES VLKPEFTVSS
PQFTDPHLYV WNVTGNRLLY RVEGVRLKTR PSQCTDYVSI KKRVEMLAKM KVTHYQFALD
WTSILPTGNL SKVNRQVLRY YRCVVSEGLK LGVFPMVTLY HPTHSHLGLP LPLLSSGGWL
NMNTAKAFQD YAELCFRELG DLVKLWITIN EPNRLSDMYN RTSNDTYRAA HNLMIAHAQV
WHLYDRQYRP VQHGAVSLSL HCDWAEPANP FVDSHWKAAE RFLQFEIAWF ADPLFKTGDY
PSVMKEYIAS KNQRGLSSSV LPRFTAKESR LVKGTVDFYA LNHFTTRFVI HKQLNTNRSV
ADRDVQFLQD ITRLSSPSRL AVTPWGVRKL LAWIRRNYRD RDIYITANGI DDLALEDDQI
RKYYLEKYVQ EALKAYLIDK VKIKGYYAFK LTEEKSKPRF GFFTSDFRAK SSVQFYSKLI
SSSGLPAENR SPACGQPAED TDCTICSFLV EKKPLIFFGC CFISTLAVLL SITVFHHQKR
RKFQKARNLQ NIPLKKGHSR VFS
//
