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O35082

- KLOT_MOUSE

UniProt

O35082 - KLOT_MOUSE

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Protein

Klotho

Gene

Kl

Organism
Mus musculus (Mouse)
Status
Reviewed - 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

Vmax=0.62 µM/h/µg enzyme1 Publication

pH dependencei

Optimum pH is 5.5.1 Publication

GO - Molecular functioni

  1. beta-glucuronidase activity Source: UniProtKB-EC
  2. fibroblast growth factor binding Source: UniProtKB
  3. fibroblast growth factor receptor binding Source: UniProtKB
  4. signal transducer activity Source: InterPro

GO - Biological processi

  1. acute inflammatory response Source: Ensembl
  2. aging Source: MGI
  3. calcium ion homeostasis Source: MGI
  4. carbohydrate metabolic process Source: InterPro
  5. energy reserve metabolic process Source: MGI
  6. insulin receptor signaling pathway Source: InterPro
  7. positive regulation of bone mineralization Source: Ensembl
  8. 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

ReactomeiREACT_196588. Constitutive PI3K/AKT Signaling in Cancer.
REACT_198525. Negative regulation of FGFR signaling.
REACT_202336. FGFR1c and Klotho ligand binding and activation.
REACT_223993. PI-3K cascade.
REACT_226341. PIP3 activates AKT signaling.
REACT_94437. SHC-mediated cascade.

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
ProteomesiUP000000589: Chromosome 5

Organism-specific databases

MGIiMGI:1101771. Kl.

Subcellular locationi

Isoform 1 : Cell membrane; Single-pass type I membrane protein
Note: Isoform 1 shedding leads to a soluble peptide.

GO - Cellular componenti

  1. extracellular region Source: MGI
  2. extracellular space Source: InterPro
  3. extracellular vesicular exosome Source: Ensembl
  4. integral component of membrane Source: MGI
  5. plasma membrane Source: UniProtKB-KW
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)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 3434Sequence AnalysisAdd
BLAST
Chaini35 – 1014980KlothoPRO_0000042247Add
BLAST
Chaini35 – ?Klotho peptidePRO_0000042248

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi161 – 1611N-linked (GlcNAc...)Sequence Analysis
Glycosylationi285 – 2851N-linked (GlcNAc...)Sequence Analysis
Glycosylationi346 – 3461N-linked (GlcNAc...)Sequence Analysis
Glycosylationi609 – 6091N-linked (GlcNAc...)Sequence Analysis
Glycosylationi614 – 6141N-linked (GlcNAc...)Sequence Analysis
Glycosylationi696 – 6961N-linked (GlcNAc...)Sequence Analysis

Post-translational modificationi

N-glycosylated.1 Publication

Keywords - PTMi

Glycoprotein

Proteomic databases

PaxDbiO35082.
PRIDEiO35082.

PTM databases

PhosphoSiteiO35082.

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

BgeeiO35082.
CleanExiMM_KL.
ExpressionAtlasiO35082. baseline and differential.
GenevestigatoriO35082.

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

Protein-protein interaction databases

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

Structurei

3D structure databases

ProteinModelPortaliO35082.
SMRiO35082. Positions 63-508, 520-949.
ModBaseiSearch...
MobiDBiSearch...

Topological domain

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini35 – 982948ExtracellularSequence AnalysisAdd
BLAST
Topological domaini1004 – 101411CytoplasmicSequence AnalysisAdd
BLAST

Transmembrane

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transmembranei983 – 100321HelicalSequence AnalysisAdd
BLAST

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni59 – 508450Glycosyl hydrolase-1 1Add
BLAST
Regioni517 – 955439Glycosyl hydrolase-1 2Add
BLAST

Domaini

Sequence similaritiesi

Keywords - Domaini

Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiCOG2723.
GeneTreeiENSGT00550000074452.
HOGENOMiHOG000060126.
HOVERGENiHBG081856.
InParanoidiO35082.
KOiK14756.
OMAiALSSHWI.
OrthoDBiEOG7MH0XV.
TreeFamiTF314803.

Family and domain databases

Gene3Di3.20.20.80. 2 hits.
InterProiIPR001360. Glyco_hydro_1.
IPR018120. Glyco_hydro_1_AS.
IPR013781. Glyco_hydro_catalytic_dom.
IPR017853. Glycoside_hydrolase_SF.
IPR028546. Klotho.
[Graphical view]
PANTHERiPTHR10353. PTHR10353. 1 hit.
PTHR10353:SF10. PTHR10353:SF10. 1 hit.
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. Align

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)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti854 – 8541L → V in BAA25308. (PubMed:9537505)Curated
Sequence conflicti948 – 9481K → R in BAA23381. (PubMed:9363890)Curated
Sequence conflicti948 – 9481K → R in BAA25308. (PubMed:9537505)Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei537 – 55014DTTLS…PNVYL → SPLTKPSVGLLLPH in isoform 2. 1 PublicationVSP_015828Add
BLAST
Alternative sequencei551 – 1014464Missing in isoform 2. 1 PublicationVSP_015829Add
BLAST

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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:
EMBL
GenBank
DDBJ
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 .
CCDSi CCDS19889.1. [O35082-1 ]
RefSeqi NP_038851.2. NM_013823.2. [O35082-1 ]
UniGenei Mm.6500.

3D structure databases

ProteinModelPortali O35082.
SMRi O35082. Positions 63-508, 520-949.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 200958. 5 interactions.
DIPi DIP-39894N.
IntActi O35082. 5 interactions.
MINTi MINT-8175062.
STRINGi 10090.ENSMUSP00000077899.

Protein family/group databases

CAZyi GH1. Glycoside Hydrolase Family 1.

PTM databases

PhosphoSitei O35082.

Proteomic databases

PaxDbi O35082.
PRIDEi O35082.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000078856 ; ENSMUSP00000077899 ; ENSMUSG00000058488 . [O35082-1 ]
GeneIDi 16591.
KEGGi mmu:16591.
UCSCi uc009auk.2. mouse. [O35082-2 ]
uc009aul.2. mouse. [O35082-1 ]

Organism-specific databases

CTDi 9365.
MGIi MGI:1101771. Kl.

Phylogenomic databases

eggNOGi COG2723.
GeneTreei ENSGT00550000074452.
HOGENOMi HOG000060126.
HOVERGENi HBG081856.
InParanoidi O35082.
KOi K14756.
OMAi ALSSHWI.
OrthoDBi EOG7MH0XV.
TreeFami TF314803.

Enzyme and pathway databases

Reactomei REACT_196588. Constitutive PI3K/AKT Signaling in Cancer.
REACT_198525. Negative regulation of FGFR signaling.
REACT_202336. FGFR1c and Klotho ligand binding and activation.
REACT_223993. PI-3K cascade.
REACT_226341. PIP3 activates AKT signaling.
REACT_94437. SHC-mediated cascade.

Miscellaneous databases

NextBioi 290141.
PROi O35082.
SOURCEi Search...

Gene expression databases

Bgeei O35082.
CleanExi MM_KL.
ExpressionAtlasi O35082. baseline and differential.
Genevestigatori O35082.

Family and domain databases

Gene3Di 3.20.20.80. 2 hits.
InterProi IPR001360. Glyco_hydro_1.
IPR018120. Glyco_hydro_1_AS.
IPR013781. Glyco_hydro_catalytic_dom.
IPR017853. Glycoside_hydrolase_SF.
IPR028546. Klotho.
[Graphical view ]
PANTHERi PTHR10353. PTHR10353. 1 hit.
PTHR10353:SF10. PTHR10353:SF10. 1 hit.
Pfami PF00232. Glyco_hydro_1. 3 hits.
[Graphical view ]
PRINTSi PR00131. GLHYDRLASE1.
SUPFAMi SSF51445. SSF51445. 2 hits.
PROSITEi PS00653. GLYCOSYL_HYDROL_F1_2. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, SUBCELLULAR LOCATION.
    Tissue: Kidney.
  2. "Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein."
    Shiraki-Iida T., Aizawa H., Matsumura Y., Sekine S., Iida A., Anazawa H., Nagai R., Kuro-o M., Nabeshima Y.
    FEBS Lett. 424:6-10(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING (ISOFORMS 1 AND 2), TISSUE SPECIFICITY.
  3. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Tissue: Brain.
  4. Cited for: TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
  5. Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  6. "Decreased insulin production and increased insulin sensitivity in the klotho mutant mouse, a novel animal model for human aging."
    Utsugi T., Ohno T., Ohyama Y., Uchiyama T., Saito Y., Matsumura Y., Aizawa H., Itoh H., Kurabayashi M., Kawazu S., Tomono S., Oka Y., Suga T., Kuro-o M., Nabeshima Y., Nagai R.
    Metabolism 49:1118-1123(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  7. "Upregulation of the klotho gene expression by thyroid hormone and during adipose differentiation in 3T3-L1 adipocytes."
    Mizuno I., Takahashi Y., Okimura Y., Kaji H., Chihara K.
    Life Sci. 68:2917-2923(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION, TISSUE SPECIFICITY.
  8. Cited for: SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
  9. "Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system."
    Tsujikawa H., Kurotaki Y., Fujimori T., Fukuda K., Nabeshima Y.
    Mol. Endocrinol. 17:2393-2403(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INDUCTION.
  10. "HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells."
    Narumiya H., Sasaki S., Kuwahara N., Irie H., Kusaba T., Kameyama H., Tamagaki K., Hatta T., Takeda K., Matsubara H.
    Cardiovasc. Res. 64:331-336(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION.
  11. "Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice."
    Li S.-A., Watanabe M., Yamada H., Nagai A., Kinuta M., Takei K.
    Cell Struct. Funct. 29:91-99(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
  12. "Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane."
    Imura A., Iwano A., Tohyama O., Tsuji Y., Nozaki K., Hashimoto N., Fujimori T., Nabeshima Y.
    FEBS Lett. 565:143-147(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: CLEAVAGE, TISSUE SPECIFICITY, SUBUNIT, GLYCOSYLATION, SUBCELLULAR LOCATION.
  13. "Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides."
    Tohyama O., Imura A., Iwano A., Freund J.-N., Henrissat B., Fujimori T., Nabeshima Y.
    J. Biol. Chem. 279:9777-9784(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: ENZYME ACTIVITY, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES.
  14. Cited for: FUNCTION, LACK OF ENZYMATIC ACTIVITY, TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
  15. "Klotho converts canonical FGF receptor into a specific receptor for FGF23."
    Urakawa I., Yamazaki Y., Shimada T., Iijima K., Hasegawa H., Okawa K., Fujita T., Fukumoto S., Yamashita T.
    Nature 444:770-774(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH FGF23 AND FGFR1.

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: October 29, 2014
This is version 118 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

External Data

Dasty 3