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Protein

Klotho

Gene

Kl

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

May have weak glycosidase activity towards glucuronylated steroids. However, it lacks essential active site Glu residues at positions 241 and 874, suggesting it may be inactive as a glycosidase in vivo. May be involved in the regulation of calcium and phosphorus homeostasis by inhibiting the synthesis of active vitamin D. Essential factor for the specific interaction between FGF23 and FGFR1.
The Klotho peptide generated by cleavage of the membrane-bound isoform may be an anti-aging circulating hormone which would extend life span by inhibiting insulin/IGF1 signaling.

Catalytic activityi

A beta-D-glucuronoside + H2O = D-glucuronate + an alcohol.1 Publication

Enzyme regulationi

Inhibited by D-saccharic acid 1,4-lactone and taurocholic acid.1 Publication

Kineticsi

  1. KM=0.249 mM for 4-methylumbelliferylglucuronide1 Publication
  2. KM=0.251 mM for estrone 3-beta-D-glucuronide1 Publication
  3. KM=0.174 mM for beta-estradiol 3-beta-D-glucuronide1 Publication
  4. KM=0.251 mM for estriol 3-beta-D-glucuronide1 Publication
  1. Vmax=0.62 µM/h/µg enzyme1 Publication

pH dependencei

Optimum pH is 5.5.1 Publication

GO - Molecular functioni

  • beta-glucosidase activity Source: GO_Central
  • beta-glucuronidase activity Source: UniProtKB-EC
  • fibroblast growth factor binding Source: UniProtKB
  • fibroblast growth factor receptor binding Source: UniProtKB
  • signal transducer activity Source: GO_Central

GO - Biological processi

  • aging Source: MGI
  • calcium ion homeostasis Source: MGI
  • carbohydrate metabolic process Source: InterPro
  • energy reserve metabolic process Source: MGI
  • glycosyl compound metabolic process Source: GO_Central
  • insulin receptor signaling pathway Source: InterPro
  • positive regulation of bone mineralization Source: MGI
  • positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Glycosidase, Hydrolase

Enzyme and pathway databases

ReactomeiR-MMU-109704. PI3K Cascade.
R-MMU-1257604. PIP3 activates AKT signaling.
R-MMU-190374. FGFR1c and Klotho ligand binding and activation.
R-MMU-5654219. Phospholipase C-mediated cascade: FGFR1.
R-MMU-5654687. Downstream signaling of activated FGFR1.
R-MMU-5654688. SHC-mediated cascade:FGFR1.
R-MMU-5654689. PI-3K cascade:FGFR1.
R-MMU-5654693. FRS-mediated FGFR1 signaling.
R-MMU-5654726. Negative regulation of FGFR1 signaling.
R-MMU-5673001. RAF/MAP kinase cascade.
R-MMU-6811558. PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.

Protein family/group databases

CAZyiGH1. Glycoside Hydrolase Family 1.

Names & Taxonomyi

Protein namesi
Recommended name:
Klotho (EC:3.2.1.31)
Cleaved into the following chain:
Gene namesi
Name:Kl
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 5

Organism-specific databases

MGIiMGI:1101771. Kl.

Subcellular locationi

Isoform 1 :
Isoform 2 :
Klotho peptide :

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini35 – 982ExtracellularSequence analysisAdd BLAST948
Transmembranei983 – 1003HelicalSequence analysisAdd BLAST21
Topological domaini1004 – 1014CytoplasmicSequence analysisAdd BLAST11

GO - Cellular componenti

  • apical plasma membrane Source: UniProtKB-SubCell
  • extracellular exosome Source: MGI
  • extracellular region Source: MGI
  • extracellular space Source: InterPro
  • integral component of membrane Source: MGI
  • integral component of plasma membrane Source: GO_Central
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane, Secreted

Pathology & Biotechi

Disruption phenotypei

Mice display a syndrome resembling to human aging, with short lifespan, infertility, atherosclerosis, skin atrophy, osteoporosis and emphysema. They have various metabolic abnormalities, including increased insulin sensitivity and decreased insulin production. Mice overexpressing Kl have increased resistance to insulin and IGF1, a lifespan extended of more than 20%, and generate fewer offspring.1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 34Sequence analysisAdd BLAST34
ChainiPRO_000004224735 – 1014KlothoAdd BLAST980
ChainiPRO_000004224835 – ?Klotho peptide

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi161N-linked (GlcNAc...)Sequence analysis1
Glycosylationi285N-linked (GlcNAc...)Sequence analysis1
Glycosylationi346N-linked (GlcNAc...)Sequence analysis1
Glycosylationi609N-linked (GlcNAc...)Sequence analysis1
Glycosylationi614N-linked (GlcNAc...)Sequence analysis1
Glycosylationi696N-linked (GlcNAc...)Sequence analysis1

Post-translational modificationi

N-glycosylated.1 Publication

Keywords - PTMi

Glycoprotein

Proteomic databases

PaxDbiO35082.
PeptideAtlasiO35082.
PRIDEiO35082.

PTM databases

iPTMnetiO35082.
PhosphoSitePlusiO35082.

Expressioni

Tissue specificityi

Membrane-bound protein is present in distal renal tubules, inner ear, ependymal cells of brain choroid plexus, elongating spermatids and mature oocytes (at protein level). Soluble peptide is present in serum (100 pM) and cerebrospinal fluid. Expressed strongly in kidney, moderately in brain choroid plexus, and at low levels in pituitary, placenta, skeletal muscle, urinary bladder, aorta, pancreas, testis, ovary, colon, thyroid gland and adipocytes.8 Publications

Developmental stagei

Not expressed in the embryo. Expressed in the kidney of newborns.1 Publication

Inductioni

Induced by 1,25-dihydroxyvitamin D3 in kidney. Down-regulated by angiotensin II and up-regulated by statins through modulation of the RhoA pathway in epithelial cells (in vitro). Isoform 1 (but not isoform 2) is up-regulated by thyroid hormone in adipocytes.3 Publications

Gene expression databases

BgeeiENSMUSG00000058488.
CleanExiMM_KL.
GenevisibleiO35082. MM.

Interactioni

Subunit structurei

Homodimer. Interacts with FGF23 and FGFR1.2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Wnt1P044262EBI-1570828,EBI-1570911
Wnt3P175534EBI-1570828,EBI-1570853
Wnt4P227242EBI-1570828,EBI-1570945
Wnt5aP227252EBI-1570828,EBI-1570983

GO - Molecular functioni

  • fibroblast growth factor binding Source: UniProtKB
  • fibroblast growth factor receptor binding Source: UniProtKB

Protein-protein interaction databases

BioGridi200958. 5 interactors.
DIPiDIP-39894N.
IntActiO35082. 5 interactors.
MINTiMINT-8175062.
STRINGi10090.ENSMUSP00000077899.

Structurei

3D structure databases

ProteinModelPortaliO35082.
SMRiO35082.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni59 – 508Glycosyl hydrolase-1 1Add BLAST450
Regioni517 – 955Glycosyl hydrolase-1 2Add BLAST439

Domaini

Sequence similaritiesi

Keywords - Domaini

Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0626. Eukaryota.
COG2723. LUCA.
GeneTreeiENSGT00550000074452.
HOGENOMiHOG000060126.
HOVERGENiHBG081856.
InParanoidiO35082.
KOiK14756.
OMAiALSSHWI.
OrthoDBiEOG091G0035.
TreeFamiTF314803.

Family and domain databases

Gene3Di3.20.20.80. 2 hits.
InterProiIPR001360. Glyco_hydro_1.
IPR033132. Glyco_hydro_1_N_CS.
IPR013781. Glyco_hydro_catalytic_dom.
IPR017853. Glycoside_hydrolase_SF.
IPR028546. Klotho.
[Graphical view]
PANTHERiPTHR10353. PTHR10353. 2 hits.
PTHR10353:SF10. PTHR10353:SF10. 2 hits.
PfamiPF00232. Glyco_hydro_1. 3 hits.
[Graphical view]
PRINTSiPR00131. GLHYDRLASE1.
SUPFAMiSSF51445. SSF51445. 2 hits.
PROSITEiPS00653. GLYCOSYL_HYDROL_F1_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O35082-1) [UniParc]FASTAAdd to basket
Also known as: Membrane-bound

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MLARAPPRRP PRLVLLRLLL LHLLLLALRA RCLSAEPGQG AQTWARFARA
60 70 80 90 100
PAPEAAGLLH DTFPDGFLWA VGSAAYQTEG GWRQHGKGAS IWDTFTHHSG
110 120 130 140 150
AAPSDSPIVV APSGAPSPPL SSTGDVASDS YNNVYRDTEG LRELGVTHYR
160 170 180 190 200
FSISWARVLP NGTAGTPNRE GLRYYRRLLE RLRELGVQPV VTLYHWDLPQ
210 220 230 240 250
RLQDTYGGWA NRALADHFRD YAELCFRHFG GQVKYWITID NPYVVAWHGY
260 270 280 290 300
ATGRLAPGVR GSSRLGYLVA HNLLLAHAKV WHLYNTSFRP TQGGRVSIAL
310 320 330 340 350
SSHWINPRRM TDYNIRECQK SLDFVLGWFA KPIFIDGDYP ESMKNNLSSL
360 370 380 390 400
LPDFTESEKR LIRGTADFFA LSFGPTLSFQ LLDPNMKFRQ LESPNLRQLL
410 420 430 440 450
SWIDLEYNHP PIFIVENGWF VSGTTKRDDA KYMYYLKKFI METLKAIRLD
460 470 480 490 500
GVDVIGYTAW SLMDGFEWHR GYSIRRGLFY VDFLSQDKEL LPKSSALFYQ
510 520 530 540 550
KLIEDNGFPP LPENQPLEGT FPCDFAWGVV DNYVQVDTTL SQFTDPNVYL
560 570 580 590 600
WDVHHSKRLI KVDGVVAKKR KPYCVDFSAI RPQITLLREM RVTHFRFSLD
610 620 630 640 650
WALILPLGNQ TQVNHTVLHF YRCMISELVH ANITPVVALW QPAAPHQGLP
660 670 680 690 700
HALAKHGAWE NPHTALAFAD YANLCFKELG HWVNLWITMN EPNTRNMTYR
710 720 730 740 750
AGHHLLRAHA LAWHLYDDKF RAAQKGKISI ALQADWIEPA CPFSQNDKEV
760 770 780 790 800
AERVLEFDIG WLAEPIFGSG DYPRVMRDWL NQKNNFLLPY FTEDEKKLVR
810 820 830 840 850
GSFDFLAVSH YTTILVDWEK EDPMKYNDYL EVQEMTDITW LNSPSQVAVV
860 870 880 890 900
PWGLRKVLNW LRFKYGDLPM YVTANGIDDD PHAEQDSLRI YYIKNYVNEA
910 920 930 940 950
LKAYVLDDIN LCGYFAYSLS DRSAPKSGFY RYAANQFEPK PSMKHYRKII
960 970 980 990 1000
DSNGFLGSGT LGRFCPEEYT VCTECGFFQT RKSLLVFISF LVFTFIISLA
1010
LIFHYSKKGQ RSYK
Note: Predominates over the secreted form by more than 10 times in all tissues examined.
Length:1,014
Mass (Da):116,398
Last modified:July 27, 2011 - v2
Checksum:i24BD772A1F81B8EC
GO
Isoform 2 (identifier: O35082-2) [UniParc]FASTAAdd to basket
Also known as: Secreted

The sequence of this isoform differs from the canonical sequence as follows:
     537-550: DTTLSQFTDPNVYL → SPLTKPSVGLLLPH
     551-1014: Missing.

Show »
Length:550
Mass (Da):62,348
Checksum:iE59AF8F24871BDC8
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti854L → V in BAA25308 (PubMed:9537505).Curated1
Sequence conflicti948K → R in BAA23381 (PubMed:9363890).Curated1
Sequence conflicti948K → R in BAA25308 (PubMed:9537505).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_015828537 – 550DTTLS…PNVYL → SPLTKPSVGLLLPH in isoform 2. 1 PublicationAdd BLAST14
Alternative sequenceiVSP_015829551 – 1014Missing in isoform 2. 1 PublicationAdd BLAST464

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB005141 mRNA. Translation: BAA23381.1.
AB010088 mRNA. Translation: BAA25307.1.
AB010091 Genomic DNA. Translation: BAA25308.1.
AB010091 Genomic DNA. Translation: BAA25309.1.
BC138258 mRNA. Translation: AAI38259.1.
BC138259 mRNA. Translation: AAI38260.1.
CCDSiCCDS19889.1. [O35082-1]
RefSeqiNP_038851.2. NM_013823.2. [O35082-1]
UniGeneiMm.6500.

Genome annotation databases

EnsembliENSMUST00000078856; ENSMUSP00000077899; ENSMUSG00000058488. [O35082-1]
GeneIDi16591.
KEGGimmu:16591.
UCSCiuc009auk.2. mouse. [O35082-2]
uc009aul.2. mouse. [O35082-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Web resourcesi

Protein Spotlight

The thread of life - Issue 65 of December 2005

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB005141 mRNA. Translation: BAA23381.1.
AB010088 mRNA. Translation: BAA25307.1.
AB010091 Genomic DNA. Translation: BAA25308.1.
AB010091 Genomic DNA. Translation: BAA25309.1.
BC138258 mRNA. Translation: AAI38259.1.
BC138259 mRNA. Translation: AAI38260.1.
CCDSiCCDS19889.1. [O35082-1]
RefSeqiNP_038851.2. NM_013823.2. [O35082-1]
UniGeneiMm.6500.

3D structure databases

ProteinModelPortaliO35082.
SMRiO35082.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi200958. 5 interactors.
DIPiDIP-39894N.
IntActiO35082. 5 interactors.
MINTiMINT-8175062.
STRINGi10090.ENSMUSP00000077899.

Protein family/group databases

CAZyiGH1. Glycoside Hydrolase Family 1.

PTM databases

iPTMnetiO35082.
PhosphoSitePlusiO35082.

Proteomic databases

PaxDbiO35082.
PeptideAtlasiO35082.
PRIDEiO35082.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000078856; ENSMUSP00000077899; ENSMUSG00000058488. [O35082-1]
GeneIDi16591.
KEGGimmu:16591.
UCSCiuc009auk.2. mouse. [O35082-2]
uc009aul.2. mouse. [O35082-1]

Organism-specific databases

CTDi9365.
MGIiMGI:1101771. Kl.

Phylogenomic databases

eggNOGiKOG0626. Eukaryota.
COG2723. LUCA.
GeneTreeiENSGT00550000074452.
HOGENOMiHOG000060126.
HOVERGENiHBG081856.
InParanoidiO35082.
KOiK14756.
OMAiALSSHWI.
OrthoDBiEOG091G0035.
TreeFamiTF314803.

Enzyme and pathway databases

ReactomeiR-MMU-109704. PI3K Cascade.
R-MMU-1257604. PIP3 activates AKT signaling.
R-MMU-190374. FGFR1c and Klotho ligand binding and activation.
R-MMU-5654219. Phospholipase C-mediated cascade: FGFR1.
R-MMU-5654687. Downstream signaling of activated FGFR1.
R-MMU-5654688. SHC-mediated cascade:FGFR1.
R-MMU-5654689. PI-3K cascade:FGFR1.
R-MMU-5654693. FRS-mediated FGFR1 signaling.
R-MMU-5654726. Negative regulation of FGFR1 signaling.
R-MMU-5673001. RAF/MAP kinase cascade.
R-MMU-6811558. PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.

Miscellaneous databases

PROiO35082.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000058488.
CleanExiMM_KL.
GenevisibleiO35082. MM.

Family and domain databases

Gene3Di3.20.20.80. 2 hits.
InterProiIPR001360. Glyco_hydro_1.
IPR033132. Glyco_hydro_1_N_CS.
IPR013781. Glyco_hydro_catalytic_dom.
IPR017853. Glycoside_hydrolase_SF.
IPR028546. Klotho.
[Graphical view]
PANTHERiPTHR10353. PTHR10353. 2 hits.
PTHR10353:SF10. PTHR10353:SF10. 2 hits.
PfamiPF00232. Glyco_hydro_1. 3 hits.
[Graphical view]
PRINTSiPR00131. GLHYDRLASE1.
SUPFAMiSSF51445. SSF51445. 2 hits.
PROSITEiPS00653. GLYCOSYL_HYDROL_F1_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiKLOT_MOUSE
AccessioniPrimary (citable) accession number: O35082
Secondary accession number(s): B2RR78, O70175, O70621
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 11, 2005
Last sequence update: July 27, 2011
Last modified: November 2, 2016
This is version 134 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Glycosyl hydrolases
    Classification of glycosyl hydrolase families and list of entries
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  3. Protein Spotlight
    Protein Spotlight articles and cited UniProtKB/Swiss-Prot entries
  4. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.