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O35082 (KLOT_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 115. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Klotho

EC=3.2.1.31

Cleaved into the following chain:

  1. Klotho peptide
Gene names
Name:Kl
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length1014 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.1 Ref.5 Ref.6 Ref.9 Ref.14 Ref.15

The Klotho peptide generated by cleavage of the membrane-bound isoform maybe an anti-aging circulating hormone which would extend life span by inhibiting insulin/IGF1 signaling. Ref.1 Ref.5 Ref.6 Ref.9 Ref.14 Ref.15

Catalytic activity

A beta-D-glucuronoside + H2O = D-glucuronate + an alcohol. Ref.13 Ref.14

Enzyme regulation

Inhibited by D-saccharic acid 1,4-lactone and taurocholic acid. Ref.13

Subunit structure

Homodimer. Interacts with FGF23 and FGFR1. Ref.12 Ref.15

Subcellular location

Isoform 1: Cell membrane; Single-pass type I membrane protein. Note: Isoform 1 shedding leads to a soluble peptide. Ref.1 Ref.4 Ref.8 Ref.11 Ref.12 Ref.14

Isoform 2: Secreted Ref.1 Ref.4 Ref.8 Ref.11 Ref.12 Ref.14.

Klotho peptide: Secreted Ref.1 Ref.4 Ref.8 Ref.11 Ref.12 Ref.14.

Tissue specificity

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. Ref.1 Ref.2 Ref.4 Ref.7 Ref.8 Ref.11 Ref.12 Ref.14

Developmental stage

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

Induction

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. Ref.7 Ref.9 Ref.10 Ref.13

Domain

Contains 2 glycosyl hydrolase 1 regions. However, the first region lacks the essential Glu active site residue at position 241, and the second one lacks the essential Glu active site residue at position 874.

Post-translational modification

N-glycosylated. Ref.12

Disruption phenotype

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. Ref.5

Sequence similarities

Belongs to the glycosyl hydrolase 1 family. Klotho subfamily.

Biophysicochemical properties

Kinetic parameters:

KM=0.249 mM for 4-methylumbelliferylglucuronide Ref.13

KM=0.251 mM for estrone 3-beta-D-glucuronide

KM=0.174 mM for beta-estradiol 3-beta-D-glucuronide

KM=0.251 mM for estriol 3-beta-D-glucuronide

Vmax=0.62 µM/h/µg enzyme

pH dependence:

Optimum pH is 5.5.

Ontologies

Keywords
   Cellular componentCell membrane
Membrane
Secreted
   Coding sequence diversityAlternative splicing
   DomainRepeat
Signal
Transmembrane
Transmembrane helix
   Molecular functionGlycosidase
Hydrolase
   PTMGlycoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processacute inflammatory response

Inferred from electronic annotation. Source: Ensembl

aging

Inferred from mutant phenotype Ref.1. Source: MGI

calcium ion homeostasis

Inferred from genetic interaction PubMed 22285620. Source: MGI

carbohydrate metabolic process

Inferred from electronic annotation. Source: InterPro

energy reserve metabolic process

Inferred from mutant phenotype Ref.5. Source: MGI

insulin receptor signaling pathway

Inferred from electronic annotation. Source: InterPro

positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway

Inferred from genetic interaction PubMed 16436388. Source: MGI

positive regulation of bone mineralization

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentextracellular region

Inferred from sequence or structural similarity Ref.2. Source: MGI

extracellular space

Inferred from electronic annotation. Source: InterPro

integral component of membrane

Inferred from sequence or structural similarity Ref.2. Source: MGI

plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionbeta-glucuronidase activity

Inferred from electronic annotation. Source: UniProtKB-EC

fibroblast growth factor binding

Inferred from physical interaction Ref.15. Source: UniProtKB

fibroblast growth factor receptor binding

Inferred from physical interaction Ref.15. Source: UniProtKB

protein binding

Inferred from physical interaction PubMed 17690294. Source: IntAct

signal transducer activity

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: O35082-1)

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.
Note: Predominates over the secreted form by more than 10 times in all tissues examined.
Isoform 2 (identifier: O35082-2)

Also known as: Secreted;

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

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 3434 Potential
Chain35 – 1014980Klotho
PRO_0000042247
Chain35 – ?Klotho peptidePRO_0000042248

Regions

Topological domain35 – 982948Extracellular Potential
Transmembrane983 – 100321Helical; Potential
Topological domain1004 – 101411Cytoplasmic Potential
Region59 – 508450Glycosyl hydrolase-1 1
Region517 – 955439Glycosyl hydrolase-1 2

Amino acid modifications

Glycosylation1611N-linked (GlcNAc...) Potential
Glycosylation2851N-linked (GlcNAc...) Potential
Glycosylation3461N-linked (GlcNAc...) Potential
Glycosylation6091N-linked (GlcNAc...) Potential
Glycosylation6141N-linked (GlcNAc...) Potential
Glycosylation6961N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence537 – 55014DTTLS…PNVYL → SPLTKPSVGLLLPH in isoform 2.
VSP_015828
Alternative sequence551 – 1014464Missing in isoform 2.
VSP_015829

Experimental info

Sequence conflict8541L → V in BAA25308. Ref.2
Sequence conflict9481K → R in BAA23381. Ref.1
Sequence conflict9481K → R in BAA25308. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (Membrane-bound) [UniParc].

Last modified July 27, 2011. Version 2.
Checksum: 24BD772A1F81B8EC

FASTA1,014116,398
        10         20         30         40         50         60 
MLARAPPRRP PRLVLLRLLL LHLLLLALRA RCLSAEPGQG AQTWARFARA PAPEAAGLLH 

        70         80         90        100        110        120 
DTFPDGFLWA VGSAAYQTEG GWRQHGKGAS IWDTFTHHSG AAPSDSPIVV APSGAPSPPL 

       130        140        150        160        170        180 
SSTGDVASDS YNNVYRDTEG LRELGVTHYR FSISWARVLP NGTAGTPNRE GLRYYRRLLE 

       190        200        210        220        230        240 
RLRELGVQPV VTLYHWDLPQ RLQDTYGGWA NRALADHFRD YAELCFRHFG GQVKYWITID 

       250        260        270        280        290        300 
NPYVVAWHGY ATGRLAPGVR GSSRLGYLVA HNLLLAHAKV WHLYNTSFRP TQGGRVSIAL 

       310        320        330        340        350        360 
SSHWINPRRM TDYNIRECQK SLDFVLGWFA KPIFIDGDYP ESMKNNLSSL LPDFTESEKR 

       370        380        390        400        410        420 
LIRGTADFFA LSFGPTLSFQ LLDPNMKFRQ LESPNLRQLL SWIDLEYNHP PIFIVENGWF 

       430        440        450        460        470        480 
VSGTTKRDDA KYMYYLKKFI METLKAIRLD GVDVIGYTAW SLMDGFEWHR GYSIRRGLFY 

       490        500        510        520        530        540 
VDFLSQDKEL LPKSSALFYQ KLIEDNGFPP LPENQPLEGT FPCDFAWGVV DNYVQVDTTL 

       550        560        570        580        590        600 
SQFTDPNVYL WDVHHSKRLI KVDGVVAKKR KPYCVDFSAI RPQITLLREM RVTHFRFSLD 

       610        620        630        640        650        660 
WALILPLGNQ TQVNHTVLHF YRCMISELVH ANITPVVALW QPAAPHQGLP HALAKHGAWE 

       670        680        690        700        710        720 
NPHTALAFAD YANLCFKELG HWVNLWITMN EPNTRNMTYR AGHHLLRAHA LAWHLYDDKF 

       730        740        750        760        770        780 
RAAQKGKISI ALQADWIEPA CPFSQNDKEV AERVLEFDIG WLAEPIFGSG DYPRVMRDWL 

       790        800        810        820        830        840 
NQKNNFLLPY FTEDEKKLVR GSFDFLAVSH YTTILVDWEK EDPMKYNDYL EVQEMTDITW 

       850        860        870        880        890        900 
LNSPSQVAVV PWGLRKVLNW LRFKYGDLPM YVTANGIDDD PHAEQDSLRI YYIKNYVNEA 

       910        920        930        940        950        960 
LKAYVLDDIN LCGYFAYSLS DRSAPKSGFY RYAANQFEPK PSMKHYRKII DSNGFLGSGT 

       970        980        990       1000       1010 
LGRFCPEEYT VCTECGFFQT RKSLLVFISF LVFTFIISLA LIFHYSKKGQ RSYK 

« Hide

Isoform 2 (Secreted) [UniParc].

Checksum: E59AF8F24871BDC8
Show »

FASTA55062,348

References

« Hide 'large scale' references
[1]"Mutation of the mouse klotho gene leads to a syndrome resembling ageing."
Kuro-o M., Matsumura Y., Aizawa H., Kawaguchi H., Suga T., Utsugi T., Ohyama Y., Kurabayashi M., Kaname T., Kume E., Iwasaki H., Iida A., Shiraki-Iida T., Nishikawa S., Nagai R., Nabeshima Y.
Nature 390:45-51(1997) [PubMed] [Europe PMC] [Abstract]
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]"Establishment of the anti-Klotho monoclonal antibodies and detection of Klotho protein in kidneys."
Kato Y., Arakawa E., Kinoshita S., Shirai A., Furuya A., Yamano K., Nakamura K., Iida A., Anazawa H., Koh N., Iwano A., Imura A., Fujimori T., Kuro-o M., Hanai N., Takeshige K., Nabeshima Y.
Biochem. Biophys. Res. Commun. 267:597-602(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[5]"Disruption of klotho gene causes an abnormal energy homeostasis in mice."
Mori K., Yahata K., Mukoyama M., Suganami T., Makino H., Nagae T., Masuzaki H., Ogawa Y., Sugawara A., Nabeshima Y., Nakao K.
Biochem. Biophys. Res. Commun. 278:665-670(2000) [PubMed] [Europe PMC] [Abstract]
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]"Expression of Klotho protein in the inner ear."
Kamemori M., Ohyama Y., Kurabayashi M., Takahashi K., Nagai R., Furuya N.
Hear. Res. 171:103-110(2002) [PubMed] [Europe PMC] [Abstract]
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]"Suppression of aging in mice by the hormone Klotho."
Kurosu H., Yamamoto M., Clark J.D., Pastor J.V., Nandi A., Gurnani P., McGuinness O.P., Chikuda H., Yamaguchi M., Kawaguchi H., Shimomura I., Takayama Y., Herz J., Kahn C.R., Rosenblatt K.P., Kuro-o M.
Science 309:1829-1833(2005) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Web resources

Protein Spotlight

The thread of life - Issue 65 of December 2005

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
CCDSCCDS19889.1. [O35082-1]
RefSeqNP_038851.2. NM_013823.2. [O35082-1]
UniGeneMm.6500.

3D structure databases

ProteinModelPortalO35082.
SMRO35082. Positions 63-508, 520-955.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid200958. 5 interactions.
DIPDIP-39894N.
IntActO35082. 5 interactions.
MINTMINT-8175062.
STRING10090.ENSMUSP00000077899.

Protein family/group databases

CAZyGH1. Glycoside Hydrolase Family 1.

PTM databases

PhosphoSiteO35082.

Proteomic databases

PaxDbO35082.
PRIDEO35082.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000078856; ENSMUSP00000077899; ENSMUSG00000058488. [O35082-1]
GeneID16591.
KEGGmmu:16591.
UCSCuc009auk.2. mouse. [O35082-2]
uc009aul.2. mouse. [O35082-1]

Organism-specific databases

CTD9365.
MGIMGI:1101771. Kl.

Phylogenomic databases

eggNOGCOG2723.
GeneTreeENSGT00550000074452.
HOGENOMHOG000060126.
HOVERGENHBG081856.
InParanoidB2RR78.
KOK14756.
OMAALSSHWI.
OrthoDBEOG7MH0XV.
TreeFamTF314803.

Gene expression databases

BgeeO35082.
CleanExMM_KL.
GenevestigatorO35082.

Family and domain databases

Gene3D3.20.20.80. 2 hits.
InterProIPR001360. Glyco_hydro_1.
IPR018120. Glyco_hydro_1_AS.
IPR013781. Glyco_hydro_catalytic_dom.
IPR017853. Glycoside_hydrolase_SF.
IPR028546. Klotho.
[Graphical view]
PANTHERPTHR10353. PTHR10353. 1 hit.
PTHR10353:SF10. PTHR10353:SF10. 1 hit.
PfamPF00232. Glyco_hydro_1. 3 hits.
[Graphical view]
PRINTSPR00131. GLHYDRLASE1.
SUPFAMSSF51445. SSF51445. 2 hits.
PROSITEPS00653. GLYCOSYL_HYDROL_F1_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio290141.
PROO35082.
SOURCESearch...

Entry information

Entry nameKLOT_MOUSE
AccessionPrimary (citable) accession number: O35082
Secondary accession number(s): B2RR78, O70175, O70621
Entry history
Integrated into UniProtKB/Swiss-Prot: October 11, 2005
Last sequence update: July 27, 2011
Last modified: July 9, 2014
This is version 115 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Protein Spotlight

Protein Spotlight articles and cited UniProtKB/Swiss-Prot entries

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot

Glycosyl hydrolases

Classification of glycosyl hydrolase families and list of entries