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Q9UEF7 (KLOT_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 111. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·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
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1012 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 239 and 872, 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 By similarity. Essential factor for the specific interaction between FGF23 and FGFR1 By similarity.

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 By similarity.

Catalytic activity

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

Subunit structure

Homodimer By similarity. Interacts with FGF23 and FGFR1 By similarity.

Subcellular location

Isoform 1: Cell membrane; Single-pass type I membrane protein. Note: Isoform 1 shedding leads to a soluble peptide. Ref.4 Ref.7

Isoform 2: Secreted Ref.4 Ref.7.

Klotho peptide: Secreted Ref.4 Ref.7.

Tissue specificity

Present in cortical renal tubules (at protein level). Soluble peptide is present in serum and cerebrospinal fluid. Expressed in kidney, placenta, small intestine and prostate. Down-regulated in renal cell carcinomas, hepatocellular carcinomas, and in chronic renal failure kidney. Ref.2 Ref.4 Ref.5 Ref.6 Ref.7

Domain

Contains 2 glycosyl hydrolase 1 regions. However, the first region lacks the essential Glu active site residue at position 239, and the second one lacks the essential Glu active site residue at position 872.

Post-translational modification

N-glycosylated By similarity.

Polymorphism

Homozygosity for KL-VS allele is associated with decreased longevity and increased cardiovascular disease risk.

Involvement in disease

Tumoral calcinosis, hyperphosphatemic, familial (HFTC) [MIM:211900]: A severe metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Some patients manifest recurrent, transient, painful swellings of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis and absence of skin involvement.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.11

Miscellaneous

Defects in KL may be a cause of chronic renal failure complications.

Sequence similarities

Belongs to the glycosyl hydrolase 1 family. Klotho subfamily.

Ontologies

Keywords
   Cellular componentCell membrane
Membrane
Secreted
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
   DomainRepeat
Signal
Transmembrane
Transmembrane helix
   LigandVitamin D
   Molecular functionGlycosidase
Hormone
Hydrolase
   PTMGlycoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processFc-epsilon receptor signaling pathway

Traceable author statement. Source: Reactome

acute inflammatory response

Inferred from electronic annotation. Source: Ensembl

aging

Inferred from mutant phenotype Ref.8. Source: UniProtKB

calcium ion homeostasis

Inferred from electronic annotation. Source: Ensembl

carbohydrate metabolic process

Inferred from electronic annotation. Source: InterPro

energy reserve metabolic process

Inferred from electronic annotation. Source: Ensembl

epidermal growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

fibroblast growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

innate immune response

Traceable author statement. Source: Reactome

insulin receptor signaling pathway

Traceable author statement. Source: Reactome

neurotrophin TRK receptor signaling pathway

Traceable author statement. Source: Reactome

phosphatidylinositol-mediated signaling

Traceable author statement. Source: Reactome

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

Inferred from electronic annotation. Source: Ensembl

positive regulation of bone mineralization

Inferred from mutant phenotype PubMed 12110410. Source: UniProtKB

   Cellular_componentextracellular region

Traceable author statement. Source: Reactome

extracellular space

Inferred from electronic annotation. Source: InterPro

extracellular vesicular exosome

Inferred from direct assay PubMed 19056867. Source: UniProt

integral component of membrane

Traceable author statement Ref.8. Source: UniProtKB

integral component of plasma membrane

Traceable author statement Ref.2. Source: ProtInc

plasma membrane

Traceable author statement. Source: Reactome

   Molecular_functionbeta-glucosidase activity

Traceable author statement Ref.1. Source: ProtInc

beta-glucuronidase activity

Inferred from electronic annotation. Source: UniProtKB-EC

fibroblast growth factor binding

Inferred from physical interaction PubMed 18829467. Source: UniProtKB

signal transducer activity

Traceable author statement Ref.1. Source: ProtInc

vitamin D binding

Inferred from electronic annotation. Source: UniProtKB-KW

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q9UEF7-1)

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.
Isoform 2 (identifier: Q9UEF7-2)

Also known as: Secreted;

The sequence of this isoform differs from the canonical sequence as follows:
     535-549: DTTLSQFTDLNVYLW → SQLTKPISSLTKPYH
     550-1012: Missing.
Note: Predominates over the membrane form in all tissues examined.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 3333 Potential
Chain34 – 1012979Klotho
PRO_0000042243
Chain34 – ?Klotho peptide By similarityPRO_0000042244

Regions

Topological domain34 – 981948Extracellular Potential
Transmembrane982 – 100221Helical; Potential
Topological domain1003 – 101210Cytoplasmic Potential
Region57 – 506450Glycosyl hydrolase-1 1
Region515 – 953439Glycosyl hydrolase-1 2

Amino acid modifications

Glycosylation1061N-linked (GlcNAc...) Potential
Glycosylation1591N-linked (GlcNAc...) Potential
Glycosylation2831N-linked (GlcNAc...) Potential
Glycosylation3441N-linked (GlcNAc...) Potential
Glycosylation6071N-linked (GlcNAc...) Potential
Glycosylation6121N-linked (GlcNAc...) Potential
Glycosylation6941N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence535 – 54915DTTLS…NVYLW → SQLTKPISSLTKPYH in isoform 2.
VSP_015824
Alternative sequence550 – 1012463Missing in isoform 2.
VSP_015825
Natural variant151P → Q. Ref.2
Corresponds to variant rs1052018 [ dbSNP | Ensembl ].
VAR_023582
Natural variant451F → V. Ref.1
Corresponds to variant rs1052019 [ dbSNP | Ensembl ].
VAR_023583
Natural variant1931H → R in HFTC; impairs the ability to form a ternary complex with FGF23 and FGFR1c; impairs KL-dependent FGF23 signaling. Ref.11
VAR_064554
Natural variant3521F → V in allele KL-VS; associated with S-370. Ref.8 Ref.9
Corresponds to variant rs9536314 [ dbSNP | Ensembl ].
VAR_023584
Natural variant3701C → S in allele KL-VS; associated with V-352. Ref.8 Ref.9
Corresponds to variant rs9527025 [ dbSNP | Ensembl ].
VAR_023585
Natural variant5141P → S.
Corresponds to variant rs3752472 [ dbSNP | Ensembl ].
VAR_049295
Natural variant9541P → L in a colorectal cancer sample; somatic mutation. Ref.10
VAR_036449

Sequences

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

Last modified October 11, 2005. Version 2.
Checksum: 62031BD73E322E63

FASTA1,012116,181
        10         20         30         40         50         60 
MPASAPPRRP RPPPPSLSLL LVLLGLGGRR LRAEPGDGAQ TWARFSRPPA PEAAGLFQGT 

        70         80         90        100        110        120 
FPDGFLWAVG SAAYQTEGGW QQHGKGASIW DTFTHHPLAP PGDSRNASLP LGAPSPLQPA 

       130        140        150        160        170        180 
TGDVASDSYN NVFRDTEALR ELGVTHYRFS ISWARVLPNG SAGVPNREGL RYYRRLLERL 

       190        200        210        220        230        240 
RELGVQPVVT LYHWDLPQRL QDAYGGWANR ALADHFRDYA ELCFRHFGGQ VKYWITIDNP 

       250        260        270        280        290        300 
YVVAWHGYAT GRLAPGIRGS PRLGYLVAHN LLLAHAKVWH LYNTSFRPTQ GGQVSIALSS 

       310        320        330        340        350        360 
HWINPRRMTD HSIKECQKSL DFVLGWFAKP VFIDGDYPES MKNNLSSILP DFTESEKKFI 

       370        380        390        400        410        420 
KGTADFFALC FGPTLSFQLL DPHMKFRQLE SPNLRQLLSW IDLEFNHPQI FIVENGWFVS 

       430        440        450        460        470        480 
GTTKRDDAKY MYYLKKFIME TLKAIKLDGV DVIGYTAWSL MDGFEWHRGY SIRRGLFYVD 

       490        500        510        520        530        540 
FLSQDKMLLP KSSALFYQKL IEKNGFPPLP ENQPLEGTFP CDFAWGVVDN YIQVDTTLSQ 

       550        560        570        580        590        600 
FTDLNVYLWD VHHSKRLIKV DGVVTKKRKS YCVDFAAIQP QIALLQEMHV THFRFSLDWA 

       610        620        630        640        650        660 
LILPLGNQSQ VNHTILQYYR CMASELVRVN ITPVVALWQP MAPNQGLPRL LARQGAWENP 

       670        680        690        700        710        720 
YTALAFAEYA RLCFQELGHH VKLWITMNEP YTRNMTYSAG HNLLKAHALA WHVYNEKFRH 

       730        740        750        760        770        780 
AQNGKISIAL QADWIEPACP FSQKDKEVAE RVLEFDIGWL AEPIFGSGDY PWVMRDWLNQ 

       790        800        810        820        830        840 
RNNFLLPYFT EDEKKLIQGT FDFLALSHYT TILVDSEKED PIKYNDYLEV QEMTDITWLN 

       850        860        870        880        890        900 
SPSQVAVVPW GLRKVLNWLK FKYGDLPMYI ISNGIDDGLH AEDDQLRVYY MQNYINEALK 

       910        920        930        940        950        960 
AHILDGINLC GYFAYSFNDR TAPRFGLYRY AADQFEPKAS MKHYRKIIDS NGFPGPETLE 

       970        980        990       1000       1010 
RFCPEEFTVC TECSFFHTRK SLLAFIAFLF FASIISLSLI FYYSKKGRRS YK 

« Hide

Isoform 2 (Secreted) [UniParc].

Checksum: CAD8D74DB71C49C6
Show »

FASTA54962,135

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] (ISOFORM 1), VARIANT VAL-45.
Tissue: Kidney.
[2]"Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein."
Matsumura Y., Aizawa H., Shiraki-Iida T., Nagai R., Kuro-o M., Nabeshima Y.
Biochem. Biophys. Res. Commun. 242:626-630(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2), VARIANT GLN-15, TISSUE SPECIFICITY.
Tissue: Hippocampus and Kidney.
[3]"The DNA sequence and analysis of human chromosome 13."
Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T. expand/collapse author list , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L., Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T.
Nature 428:522-528(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[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]"Molecular cloning and expression of a novel klotho-related protein."
Yahata K., Mori K., Arai H., Koide S., Ogawa Y., Mukoyama M., Sugawara A., Ozaki S., Tanaka I., Nabeshima Y., Nakao K.
J. Mol. Med. 78:389-394(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[6]"Severely reduced production of klotho in human chronic renal failure kidney."
Koh N., Fujimori T., Nishiguchi S., Tamori A., Shiomi S., Nakatani T., Sugimura K., Kishimoto T., Kinoshita S., Kuroki T., Nabeshima Y.
Biochem. Biophys. Res. Commun. 280:1015-1020(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY, INVOLVEMENT IN RENAL FAILURE.
[7]"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: TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[8]"Association of human aging with a functional variant of klotho."
Arking D.E., Krebsova A., Macek M. Sr., Macek M. Jr., Arking A., Mian I.S., Fried L., Hamosh A., Dey S., McIntosh I., Dietz H.C.
Proc. Natl. Acad. Sci. U.S.A. 99:856-861(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS KL-VS VAL-352 AND SER-370.
[9]"Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity."
Arking D.E., Atzmon G., Arking A., Barzilai N., Dietz H.C.
Circ. Res. 96:412-418(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS KL-VS VAL-352 AND SER-370.
[10]"The consensus coding sequences of human breast and colorectal cancers."
Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. expand/collapse author list , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E.
Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT [LARGE SCALE ANALYSIS] LEU-954.
[11]"A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis."
Ichikawa S., Imel E.A., Kreiter M.L., Yu X., Mackenzie D.S., Sorenson A.H., Goetz R., Mohammadi M., White K.E., Econs M.J.
J. Clin. Invest. 117:2684-2691(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HFTC ARG-193.
+Additional computationally mapped references.

Web resources

Protein Spotlight

The thread of life - Issue 65 of December 2005

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB005142 mRNA. Translation: BAA23382.1.
AB009667 Genomic DNA. Translation: BAA24940.1.
AB009667 Genomic DNA. Translation: BAA24941.1.
AL161898 Genomic DNA. Translation: CAH71888.1.
Z92540 Genomic DNA. Translation: CAC94767.1.
Z84483 Genomic DNA. Translation: CAC94773.1.
PIRJC5925.
JC5926.
RefSeqNP_004786.2. NM_004795.3.
UniGeneHs.524953.

3D structure databases

ProteinModelPortalQ9UEF7.
SMRQ9UEF7. Positions 61-506, 519-953.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActQ9UEF7. 1 interaction.
STRING9606.ENSP00000369442.

Protein family/group databases

CAZyGH1. Glycoside Hydrolase Family 1.

PTM databases

PhosphoSiteQ9UEF7.

Polymorphism databases

DMDM77416517.

Proteomic databases

PaxDbQ9UEF7.
PRIDEQ9UEF7.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000380099; ENSP00000369442; ENSG00000133116. [Q9UEF7-1]
GeneID9365.
KEGGhsa:9365.
UCSCuc001uus.3. human. [Q9UEF7-1]

Organism-specific databases

CTD9365.
GeneCardsGC13P033590.
H-InvDBHIX0011224.
HGNCHGNC:6344. KL.
HPAHPA023480.
MIM211900. phenotype.
604824. gene+phenotype.
neXtProtNX_Q9UEF7.
Orphanet306661. Hypercalcemic tumoral calcinosis.
PharmGKBPA30130.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG2723.
HOGENOMHOG000060126.
HOVERGENHBG081856.
InParanoidQ9UEF7.
KOK14756.
OMAALSSHWI.
OrthoDBEOG7MH0XV.
PhylomeDBQ9UEF7.
TreeFamTF314803.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.

Gene expression databases

ArrayExpressQ9UEF7.
BgeeQ9UEF7.
CleanExHS_KL.
GenevestigatorQ9UEF7.

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

GeneWikiKlotho_(biology).
GenomeRNAi9365.
NextBio35073.
PMAP-CutDBQ9UEF7.
PROQ9UEF7.
SOURCESearch...

Entry information

Entry nameKLOT_HUMAN
AccessionPrimary (citable) accession number: Q9UEF7
Secondary accession number(s): Q5VZ95 expand/collapse secondary AC list , Q96KV5, Q96KW5, Q9UEI9, Q9Y4F0
Entry history
Integrated into UniProtKB/Swiss-Prot: October 11, 2005
Last sequence update: October 11, 2005
Last modified: April 16, 2014
This is version 111 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Protein Spotlight

Protein Spotlight articles and cited UniProtKB/Swiss-Prot entries

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 13

Human chromosome 13: entries, gene names and cross-references to MIM

Glycosyl hydrolases

Classification of glycosyl hydrolase families and list of entries