KLOTB_HUMAN
ID KLOTB_HUMAN Reviewed; 1044 AA.
AC Q86Z14; Q2M3K8;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2003, sequence version 1.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Beta-klotho;
DE Short=BKL;
DE Short=BetaKlotho;
DE AltName: Full=Klotho beta-like protein;
GN Name=KLB;
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 [MRNA].
RA Hayashi A., Saito T.;
RT "Klotho beta like protein.";
RL Submitted (FEB-2002) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
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 INTERACTION WITH FGF19 AND FGF21.
RX PubMed=18829467; DOI=10.1074/jbc.m803319200;
RA Wu X., Lemon B., Li X., Gupte J., Weiszmann J., Stevens J., Hawkins N.,
RA Shen W., Lindberg R., Chen J.-L., Tian H., Li Y.;
RT "C-terminal tail of FGF19 determines its specificity toward Klotho co-
RT receptors.";
RL J. Biol. Chem. 283:33304-33309(2008).
RN [4]
RP INTERACTION WITH FGF21.
RX PubMed=19117008; DOI=10.1002/jcp.21675;
RA Micanovic R., Raches D.W., Dunbar J.D., Driver D.A., Bina H.A.,
RA Dickinson C.D., Kharitonenkov A.;
RT "Different roles of N- and C- termini in the functional activity of
RT FGF21.";
RL J. Cell. Physiol. 219:227-234(2009).
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 (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Interacts with FGFR1 and FGFR4 (By similarity). Interacts with
CC FGF19; this interaction is direct. Interacts (via C-terminus) with
CC FGF21; this interaction is direct. {ECO:0000250,
CC ECO:0000269|PubMed:18829467, ECO:0000269|PubMed:19117008}.
CC -!- INTERACTION:
CC Q86Z14; Q9NSA1: FGF21; NbExp=2; IntAct=EBI-8515198, EBI-3909329;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000305}; Single-pass type III
CC membrane protein {ECO:0000305}.
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 889. These domains are therefore predicted to be inactive.
CC -!- SIMILARITY: Belongs to the glycosyl hydrolase 1 family. Klotho
CC subfamily. {ECO:0000305}.
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DR EMBL; AB079373; BAC56857.1; -; mRNA.
DR EMBL; BC104871; AAI04872.1; -; mRNA.
DR EMBL; BC113653; AAI13654.1; -; mRNA.
DR CCDS; CCDS3451.1; -.
DR RefSeq; NP_783864.1; NM_175737.3.
DR PDB; 5VAK; X-ray; 1.70 A; A=30-522.
DR PDB; 5VAN; X-ray; 2.20 A; A=30-983.
DR PDB; 5VAQ; X-ray; 2.61 A; A=30-983.
DR PDB; 5WI9; X-ray; 2.70 A; A/B=52-508.
DR PDB; 6NFJ; X-ray; 3.19 A; A/D=30-984.
DR PDBsum; 5VAK; -.
DR PDBsum; 5VAN; -.
DR PDBsum; 5VAQ; -.
DR PDBsum; 5WI9; -.
DR PDBsum; 6NFJ; -.
DR AlphaFoldDB; Q86Z14; -.
DR SMR; Q86Z14; -.
DR BioGRID; 127468; 7.
DR CORUM; Q86Z14; -.
DR IntAct; Q86Z14; 6.
DR MINT; Q86Z14; -.
DR STRING; 9606.ENSP00000257408; -.
DR ChEMBL; CHEMBL4630720; -.
DR CAZy; GH1; Glycoside Hydrolase Family 1.
DR TCDB; 8.A.49.1.2; the klotho auxiliary protein (klotho) family.
DR GlyConnect; 1040; 1 N-Linked glycan (1 site).
DR GlyGen; Q86Z14; 12 sites, 1 N-linked glycan (1 site).
DR iPTMnet; Q86Z14; -.
DR PhosphoSitePlus; Q86Z14; -.
DR BioMuta; KLB; -.
DR DMDM; 74750586; -.
DR jPOST; Q86Z14; -.
DR MassIVE; Q86Z14; -.
DR MaxQB; Q86Z14; -.
DR PaxDb; Q86Z14; -.
DR PeptideAtlas; Q86Z14; -.
DR PRIDE; Q86Z14; -.
DR ProteomicsDB; 70496; -.
DR ABCD; Q86Z14; 3 sequenced antibodies.
DR Antibodypedia; 10542; 136 antibodies from 22 providers.
DR DNASU; 152831; -.
DR Ensembl; ENST00000257408.5; ENSP00000257408.4; ENSG00000134962.7.
DR GeneID; 152831; -.
DR KEGG; hsa:152831; -.
DR MANE-Select; ENST00000257408.5; ENSP00000257408.4; NM_175737.4; NP_783864.1.
DR UCSC; uc003gua.4; human.
DR CTD; 152831; -.
DR DisGeNET; 152831; -.
DR GeneCards; KLB; -.
DR HGNC; HGNC:15527; KLB.
DR HPA; ENSG00000134962; Group enriched (adipose tissue, liver, pancreas).
DR MIM; 611135; gene.
DR neXtProt; NX_Q86Z14; -.
DR OpenTargets; ENSG00000134962; -.
DR PharmGKB; PA142671586; -.
DR VEuPathDB; HostDB:ENSG00000134962; -.
DR eggNOG; KOG0626; Eukaryota.
DR GeneTree; ENSGT00940000157489; -.
DR HOGENOM; CLU_001859_5_2_1; -.
DR InParanoid; Q86Z14; -.
DR OMA; ARMKVTH; -.
DR OrthoDB; 408001at2759; -.
DR PhylomeDB; Q86Z14; -.
DR TreeFam; TF314803; -.
DR PathwayCommons; Q86Z14; -.
DR Reactome; R-HSA-109704; PI3K Cascade.
DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling.
DR Reactome; R-HSA-1307965; betaKlotho-mediated ligand binding.
DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer.
DR Reactome; R-HSA-5654228; Phospholipase C-mediated cascade, FGFR4.
DR Reactome; R-HSA-5654712; FRS-mediated FGFR4 signaling.
DR Reactome; R-HSA-5654719; SHC-mediated cascade:FGFR4.
DR Reactome; R-HSA-5654720; PI-3K cascade:FGFR4.
DR Reactome; R-HSA-5654733; Negative regulation of FGFR4 signaling.
DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade.
DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR SignaLink; Q86Z14; -.
DR BioGRID-ORCS; 152831; 23 hits in 1060 CRISPR screens.
DR ChiTaRS; KLB; human.
DR GenomeRNAi; 152831; -.
DR Pharos; Q86Z14; Tbio.
DR PRO; PR:Q86Z14; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q86Z14; protein.
DR Bgee; ENSG00000134962; Expressed in sperm and 104 other tissues.
DR Genevisible; Q86Z14; HS.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0017134; F:fibroblast growth factor binding; IPI:UniProtKB.
DR GO; GO:0005104; F:fibroblast growth factor receptor binding; IPI:UniProtKB.
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; IBA:GO_Central.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IEA:Ensembl.
DR GO; GO:0090080; P:positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway; IEA:Ensembl.
DR InterPro; IPR001360; Glyco_hydro_1.
DR InterPro; IPR017853; Glycoside_hydrolase_SF.
DR PANTHER; PTHR10353; PTHR10353; 2.
DR Pfam; PF00232; Glyco_hydro_1; 3.
DR PRINTS; PR00131; GLHYDRLASE1.
DR SUPFAM; SSF51445; SSF51445; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Glycoprotein; Membrane; Reference proteome;
KW Repeat; Transmembrane; Transmembrane helix.
FT CHAIN 1..1044
FT /note="Beta-klotho"
FT /id="PRO_0000063905"
FT TOPO_DOM 1..996
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 997..1017
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1018..1044
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 77..508
FT /note="Glycosyl hydrolase-1 1"
FT REGION 517..967
FT /note="Glycosyl hydrolase-1 2"
FT CARBOHYD 71
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 120
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 125
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 308
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 391
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 554
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 611
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 702
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 706
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 971
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VARIANT 65
FT /note="P -> A (in dbSNP:rs34905034)"
FT /id="VAR_061207"
FT VARIANT 728
FT /note="R -> Q (in dbSNP:rs17618244)"
FT /id="VAR_034053"
FT VARIANT 747
FT /note="A -> V (in dbSNP:rs35372803)"
FT /id="VAR_034054"
FT VARIANT 906
FT /note="Y -> H (in dbSNP:rs17618262)"
FT /id="VAR_049296"
FT VARIANT 1020
FT /note="Q -> K (in dbSNP:rs4975017)"
FT /id="VAR_034055"
FT HELIX 56..61
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 86..90
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 93..96
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 102..104
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 109..117
FT /evidence="ECO:0007829|PDB:5VAK"
FT TURN 130..132
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 134..144
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 147..152
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 155..158
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 162..166
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 169..184
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 188..196
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 200..206
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 208..210
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 214..229
FT /evidence="ECO:0007829|PDB:5VAK"
FT TURN 230..232
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 235..240
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 242..250
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 263..287
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 289..292
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 295..301
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 304..306
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 313..326
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 328..335
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 336..339
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 342..347
FT /evidence="ECO:0007829|PDB:5VAK"
FT TURN 348..351
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 357..363
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 368..375
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 376..378
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 382..384
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 390..393
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 396..406
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 411..417
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 430..450
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 453..460
FT /evidence="ECO:0007829|PDB:5VAK"
FT HELIX 468..470
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 473..475
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 478..480
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 485..487
FT /evidence="ECO:0007829|PDB:5VAN"
FT STRAND 490..492
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 494..505
FT /evidence="ECO:0007829|PDB:5VAK"
FT STRAND 526..533
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 576..578
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 580..589
FT /evidence="ECO:0007829|PDB:5VAN"
FT STRAND 595..600
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 603..606
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 612..614
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 617..632
FT /evidence="ECO:0007829|PDB:5VAN"
FT STRAND 636..642
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 653..657
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 660..662
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 665..681
FT /evidence="ECO:0007829|PDB:5VAN"
FT TURN 682..684
FT /evidence="ECO:0007829|PDB:5VAN"
FT STRAND 687..692
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 694..696
FT /evidence="ECO:0007829|PDB:5VAN"
FT TURN 698..700
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 705..729
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 731..734
FT /evidence="ECO:0007829|PDB:5VAN"
FT STRAND 737..743
FT /evidence="ECO:0007829|PDB:5VAN"
FT STRAND 746..751
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 755..768
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 770..777
FT /evidence="ECO:0007829|PDB:5VAN"
FT STRAND 779..781
FT /evidence="ECO:0007829|PDB:6NFJ"
FT HELIX 784..795
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 808..814
FT /evidence="ECO:0007829|PDB:5VAN"
FT STRAND 819..824
FT /evidence="ECO:0007829|PDB:5VAN"
FT STRAND 828..833
FT /evidence="ECO:0007829|PDB:5VAN"
FT STRAND 838..840
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 841..844
FT /evidence="ECO:0007829|PDB:5VAN"
FT STRAND 847..850
FT /evidence="ECO:0007829|PDB:5VAN"
FT STRAND 853..855
FT /evidence="ECO:0007829|PDB:6NFJ"
FT HELIX 866..880
FT /evidence="ECO:0007829|PDB:5VAN"
FT STRAND 885..889
FT /evidence="ECO:0007829|PDB:5VAN"
FT HELIX 901..919
FT /evidence="ECO:0007829|PDB:5VAN"
FT STRAND 925..931
FT /evidence="ECO:0007829|PDB:5VAN"
FT STRAND 937..939
FT /evidence="ECO:0007829|PDB:6NFJ"
FT STRAND 943..945
FT /evidence="ECO:0007829|PDB:6NFJ"
FT HELIX 954..964
FT /evidence="ECO:0007829|PDB:5VAN"
SQ SEQUENCE 1044 AA; 119808 MW; 6EA0198250F8928F CRC64;
MKPGCAAGSP GNEWIFFSTD EITTRYRNTM SNGGLQRSVI LSALILLRAV TGFSGDGRAI
WSKNPNFTPV NESQLFLYDT FPKNFFWGIG TGALQVEGSW KKDGKGPSIW DHFIHTHLKN
VSSTNGSSDS YIFLEKDLSA LDFIGVSFYQ FSISWPRLFP DGIVTVANAK GLQYYSTLLD
ALVLRNIEPI VTLYHWDLPL ALQEKYGGWK NDTIIDIFND YATYCFQMFG DRVKYWITIH
NPYLVAWHGY GTGMHAPGEK GNLAAVYTVG HNLIKAHSKV WHNYNTHFRP HQKGWLSITL
GSHWIEPNRS ENTMDIFKCQ QSMVSVLGWF ANPIHGDGDY PEGMRKKLFS VLPIFSEAEK
HEMRGTADFF AFSFGPNNFK PLNTMAKMGQ NVSLNLREAL NWIKLEYNNP RILIAENGWF
TDSRVKTEDT TAIYMMKNFL SQVLQAIRLD EIRVFGYTAW SLLDGFEWQD AYTIRRGLFY
VDFNSKQKER KPKSSAHYYK QIIRENGFSL KESTPDVQGQ FPCDFSWGVT ESVLKPESVA
SSPQFSDPHL YVWNATGNRL LHRVEGVRLK TRPAQCTDFV NIKKQLEMLA RMKVTHYRFA
LDWASVLPTG NLSAVNRQAL RYYRCVVSEG LKLGISAMVT LYYPTHAHLG LPEPLLHADG
WLNPSTAEAF QAYAGLCFQE LGDLVKLWIT INEPNRLSDI YNRSGNDTYG AAHNLLVAHA
LAWRLYDRQF RPSQRGAVSL SLHADWAEPA NPYADSHWRA AERFLQFEIA WFAEPLFKTG
DYPAAMREYI ASKHRRGLSS SALPRLTEAE RRLLKGTVDF CALNHFTTRF VMHEQLAGSR
YDSDRDIQFL QDITRLSSPT RLAVIPWGVR KLLRWVRRNY GDMDIYITAS GIDDQALEDD
RLRKYYLGKY LQEVLKAYLI DKVRIKGYYA FKLAEEKSKP RFGFFTSDFK AKSSIQFYNK
VISSRGFPFE NSSSRCSQTQ ENTECTVCLF LVQKKPLIFL GCCFFSTLVL LLSIAIFQRQ
KRRKFWKAKN LQHIPLKKGK RVVS
