KLOT_RAT
ID KLOT_RAT Reviewed; 1014 AA.
AC Q9Z2Y9;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 150.
DE RecName: Full=Klotho;
DE EC=3.2.1.31;
DE Contains:
DE RecName: Full=Klotho peptide;
DE Flags: Precursor;
GN Name=Kl;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, INDUCTION, AND
RP DEVELOPMENTAL STAGE.
RC TISSUE=Lung;
RX PubMed=9791011; DOI=10.1006/bbrc.1998.9576;
RA Ohyama Y., Kurabayashi M., Masuda H., Nakamura T., Aihara Y., Kaname T.,
RA Suga T., Arai M., Aizawa H., Matsumura Y., Kuro-o M., Nabeshima Y.,
RA Nagai R.;
RT "Molecular cloning of rat klotho cDNA: markedly decreased expression of
RT klotho by acute inflammatory stress.";
RL Biochem. Biophys. Res. Commun. 251:920-925(1998).
RN [2]
RP INDUCTION.
RX PubMed=9731228; DOI=10.1006/bbrc.1998.9246;
RA Aizawa H., Saito Y., Nakamura T., Inoue M., Imanari T., Ohyama Y.,
RA Matsumura Y., Masuda H., Oba S., Mise N., Kimura K., Hasegawa A.,
RA Kurabayashi M., Kuro-o M., Nabeshima Y., Nagai R.;
RT "Downregulation of the Klotho gene in the kidney under sustained
RT circulatory stress in rats.";
RL Biochem. Biophys. Res. Commun. 249:865-871(1998).
RN [3]
RP TISSUE SPECIFICITY.
RX PubMed=10631108; DOI=10.1006/bbrc.1999.2009;
RA Kato Y., Arakawa E., Kinoshita S., Shirai A., Furuya A., Yamano K.,
RA Nakamura K., Iida A., Anazawa H., Koh N., Iwano A., Imura A., Fujimori T.,
RA Kuro-o M., Hanai N., Takeshige K., Nabeshima Y.;
RT "Establishment of the anti-Klotho monoclonal antibodies and detection of
RT Klotho protein in kidneys.";
RL Biochem. Biophys. Res. Commun. 267:597-602(2000).
RN [4]
RP INDUCTION.
RX PubMed=10892340; DOI=10.1007/s000180050038;
RA Nagai R., Saito Y., Ohyama Y., Aizawa H., Suga T., Nakamura T.,
RA Kurabayashi M., Kuroo M.;
RT "Endothelial dysfunction in the klotho mouse and downregulation of klotho
RT gene expression in various animal models of vascular and metabolic
RT diseases.";
RL Cell. Mol. Life Sci. 57:738-746(2000).
RN [5]
RP INDUCTION.
RX PubMed=11967236; DOI=10.1161/01.hyp.0000013734.33441.ea;
RA Mitani H., Ishizaka N., Aizawa T., Ohno M., Usui S., Suzuki T., Amaki T.,
RA Mori I., Nakamura Y., Sato M., Nangaku M., Hirata Y., Nagai R.;
RT "In vivo klotho gene transfer ameliorates angiotensin II-induced renal
RT damage.";
RL Hypertension 39:838-843(2002).
RN [6]
RP INDUCTION.
RX PubMed=12965205; DOI=10.1016/s0014-5793(03)00894-9;
RA Saito K., Ishizaka N., Mitani H., Ohno M., Nagai R.;
RT "Iron chelation and a free radical scavenger suppress angiotensin II-
RT induced downregulation of klotho, an anti-aging gene, in rat.";
RL FEBS Lett. 551:58-62(2003).
RN [7]
RP TISSUE SPECIFICITY.
RX PubMed=17992255; DOI=10.1172/jci32409;
RA Ben-Dov I.Z., Galitzer H., Lavi-Moshayoff V., Goetz R., Kuro-o M.,
RA Mohammadi M., Sirkis R., Naveh-Many T., Silver J.;
RT "The parathyroid is a target organ for FGF23 in rats.";
RL J. Clin. Invest. 117:4003-4008(2007).
CC -!- FUNCTION: May have weak glycosidase activity towards glucuronylated
CC steroids. However, it lacks essential active site Glu residues at
CC positions 241 and 874, suggesting it may be inactive as a glycosidase
CC in vivo. May be involved in the regulation of calcium and phosphorus
CC homeostasis by inhibiting the synthesis of active vitamin D (By
CC similarity). Essential factor for the specific interaction between
CC FGF23 and FGFR1 (By similarity). {ECO:0000250}.
CC -!- FUNCTION: The Klotho peptide generated by cleavage of the membrane-
CC bound isoform may be an anti-aging circulating hormone which would
CC extend life span by inhibiting insulin/IGF1 signaling. {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a beta-D-glucuronoside + H2O = an alcohol + D-glucuronate;
CC Xref=Rhea:RHEA:17633, ChEBI:CHEBI:15377, ChEBI:CHEBI:30879,
CC ChEBI:CHEBI:58720, ChEBI:CHEBI:83411; EC=3.2.1.31;
CC -!- SUBUNIT: Homodimer. Interacts with FGF23 and FGFR1. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:O35082};
CC Single-pass type I membrane protein {ECO:0000250|UniProtKB:O35082}.
CC Apical cell membrane {ECO:0000250|UniProtKB:O35082}; Single-pass type I
CC membrane protein {ECO:0000250|UniProtKB:O35082}. Note=Its shedding
CC leads to a soluble peptide. {ECO:0000250|UniProtKB:O35082}.
CC -!- SUBCELLULAR LOCATION: [Klotho peptide]: Secreted
CC {ECO:0000250|UniProtKB:O35082}.
CC -!- TISSUE SPECIFICITY: Present in cortical renal tubules and the
CC parathyroid (at protein level). Strongly expressed in kidney. Expressed
CC at low levels in brain, lung, intestine and ovaries.
CC {ECO:0000269|PubMed:10631108, ECO:0000269|PubMed:17992255,
CC ECO:0000269|PubMed:9791011}.
CC -!- DEVELOPMENTAL STAGE: Expressed faintly from E18 in the kidney.
CC Expression increases in the kidney after 4 days of age.
CC {ECO:0000269|PubMed:9791011}.
CC -!- INDUCTION: Down-regulated by angiotensin II and iron overload (at
CC protein level). Down-regulated by acute inflammatory stress, and in
CC models for long-term hypertension, diabetes mellitus and chronic renal
CC failure. {ECO:0000269|PubMed:10892340, ECO:0000269|PubMed:11967236,
CC ECO:0000269|PubMed:12965205, ECO:0000269|PubMed:9731228,
CC ECO:0000269|PubMed:9791011}.
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 874.
CC -!- PTM: N-glycosylated. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the glycosyl hydrolase 1 family. Klotho
CC subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=The thread of life - Issue
CC 65 of December 2005;
CC URL="https://web.expasy.org/spotlight/back_issues/065";
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DR EMBL; AB017820; BAA34740.1; -; mRNA.
DR PIR; JE0333; JE0333.
DR RefSeq; NP_112626.1; NM_031336.1.
DR AlphaFoldDB; Q9Z2Y9; -.
DR SMR; Q9Z2Y9; -.
DR STRING; 10116.ENSRNOP00000001449; -.
DR CAZy; GH1; Glycoside Hydrolase Family 1.
DR GlyGen; Q9Z2Y9; 6 sites.
DR PaxDb; Q9Z2Y9; -.
DR PRIDE; Q9Z2Y9; -.
DR ABCD; Q9Z2Y9; 1 sequenced antibody.
DR Ensembl; ENSRNOT00000001449; ENSRNOP00000001449; ENSRNOG00000001092.
DR GeneID; 83504; -.
DR KEGG; rno:83504; -.
DR UCSC; RGD:620396; rat.
DR CTD; 9365; -.
DR RGD; 620396; Kl.
DR eggNOG; KOG0626; Eukaryota.
DR GeneTree; ENSGT00940000157614; -.
DR HOGENOM; CLU_001859_5_2_1; -.
DR InParanoid; Q9Z2Y9; -.
DR OrthoDB; 408001at2759; -.
DR PhylomeDB; Q9Z2Y9; -.
DR TreeFam; TF314803; -.
DR Reactome; R-RNO-109704; PI3K Cascade.
DR Reactome; R-RNO-1257604; PIP3 activates AKT signaling.
DR Reactome; R-RNO-190374; FGFR1c and Klotho ligand binding and activation.
DR Reactome; R-RNO-5654219; Phospholipase C-mediated cascade: FGFR1.
DR Reactome; R-RNO-5654687; Downstream signaling of activated FGFR1.
DR Reactome; R-RNO-5654688; SHC-mediated cascade:FGFR1.
DR Reactome; R-RNO-5654689; PI-3K cascade:FGFR1.
DR Reactome; R-RNO-5654693; FRS-mediated FGFR1 signaling.
DR Reactome; R-RNO-5654726; Negative regulation of FGFR1 signaling.
DR Reactome; R-RNO-5673001; RAF/MAP kinase cascade.
DR Reactome; R-RNO-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR PRO; PR:Q9Z2Y9; -.
DR Proteomes; UP000002494; Chromosome 12.
DR Genevisible; Q9Z2Y9; RN.
DR GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005615; C:extracellular space; IEA:InterPro.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; TAS:RGD.
DR GO; GO:0004566; F:beta-glucuronidase activity; IEA:UniProtKB-EC.
DR GO; GO:0017134; F:fibroblast growth factor binding; ISO:RGD.
DR GO; GO:0005104; F:fibroblast growth factor receptor binding; ISO:RGD.
DR GO; GO:0002526; P:acute inflammatory response; IDA:RGD.
DR GO; GO:0007568; P:aging; IEP:RGD.
DR GO; GO:0055074; P:calcium ion homeostasis; ISO:RGD.
DR GO; GO:0005975; P:carbohydrate metabolic process; IEA:InterPro.
DR GO; GO:0006112; P:energy reserve metabolic process; ISO:RGD.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IEA:InterPro.
DR GO; GO:0003085; P:negative regulation of systemic arterial blood pressure; IMP:RGD.
DR GO; GO:0042421; P:norepinephrine biosynthetic process; IMP:RGD.
DR GO; GO:0030501; P:positive regulation of bone mineralization; ISO:RGD.
DR GO; GO:0090080; P:positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway; ISO:RGD.
DR GO; GO:0014823; P:response to activity; IEP:RGD.
DR GO; GO:1990776; P:response to angiotensin; IEP:RGD.
DR GO; GO:0071774; P:response to fibroblast growth factor; IEP:RGD.
DR GO; GO:0033280; P:response to vitamin D; IEP:RGD.
DR InterPro; IPR001360; Glyco_hydro_1.
DR InterPro; IPR033132; Glyco_hydro_1_N_CS.
DR InterPro; IPR017853; Glycoside_hydrolase_SF.
DR InterPro; IPR028546; Klotho.
DR PANTHER; PTHR10353; PTHR10353; 5.
DR PANTHER; PTHR10353:SF10; PTHR10353:SF10; 5.
DR Pfam; PF00232; Glyco_hydro_1; 3.
DR PRINTS; PR00131; GLHYDRLASE1.
DR SUPFAM; SSF51445; SSF51445; 2.
DR PROSITE; PS00653; GLYCOSYL_HYDROL_F1_2; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Glycoprotein; Glycosidase; Hydrolase; Membrane;
KW Reference proteome; Repeat; Secreted; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..34
FT /evidence="ECO:0000255"
FT CHAIN 35..1014
FT /note="Klotho"
FT /id="PRO_0000042249"
FT CHAIN 35..?
FT /note="Klotho peptide"
FT /evidence="ECO:0000250"
FT /id="PRO_0000042250"
FT TOPO_DOM 35..983
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 984..1004
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1005..1014
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 59..508
FT /note="Glycosyl hydrolase-1 1"
FT REGION 517..955
FT /note="Glycosyl hydrolase-1 2"
FT CARBOHYD 161
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 285
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 346
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 614
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 696
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
SQ SEQUENCE 1014 AA; 116800 MW; 16F3B57581AC1DF0 CRC64;
MPARAPPRRL PRLLLLRLLS LHLLLLTLRA RCLSAEPGQG AQTWARFARP PVPEASGLLH
DTFPDGFLWA VGSAAYQTEG GWRQHGKGAS IWDTFTHHPR AIPEDSPIVM APSGAPLPPL
PSTGDVASDS YNNVYRDTEG LRELGVTHYR FSISWARVLP NGTAGTPNRE GLRYYRRLLE
RLRELGVQPV VTLYHWDLPQ RLQDTYGGWA NRALADHFRD YAELCFRHFG GQVKYWITID
NPYVVAWHGY ATGRLAPGVR GSSRLGYLVA HNLLLAHAKV WRLYNTSFRP TQGGRVSIAL
GSHWITPRRM TDYHIRECQK SLDFVLGWFA KPIFIDGDYP KSMKNNLSSL LPDFTESEKR
FIRGTADFFA LSFGPTLSFQ LLDPSMKFRQ LESPSLRQLL SWIDLEYNHP QIFIVENGWF
VSGTTRRDDA KYMYYLKKFI MESLKAIRLD GVDVIGYTAW SLMDGFEWHR GYSIRRGLFY
VDFLSQDKEL LPKSSALFYQ KLIENNGFPP LPENQPLEGT FPCDFAWGVV DNYIQVDPTL
SQFTDPNVYL WDVHHSKRLI KVDGVVAKKR KPYCVDFSAI RPQITLLREM RVTHFRFSLD
WALILPLGNQ TQVNRTVLHF YRCMVSELVH ANITPVVALW QPATPHQGLP HALAKHGAWE
NPHTALAFAD YANLCFEELG HWVKFWITIN EPNSRNMTYR AGHHLLKAHA LAWHLYDDKF
RAAQKGKISI ALQVDWIEPA CPFSQKDKEV AERVLEFDVG WLAEPIFGSG DYPHVMREWL
NQKNNFLLPY FTEDEKKLIR GSFDFLALSH YTTILVDWEK EDPIKYNDYL EVQEMTDITW
LNSPNQVAVV PWGLRKALNW LRFKYGDLPM FVTANGIDDD PHAEQDSLRM YYIKNYVNEA
LKAYVLDGIN LCGYFAYSLS DRSVPKSGFY RYAANQFEPK PSIKHYRKII DNNGFLGSGT
LGRFCPEEYT VCTGCGFFQT RKSLLAFISF LVFAFVTSLA LIYYYSKKGR RRYK
