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Protein

Klotho

Gene

KL

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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).By similarity
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.By similarity

Miscellaneous

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

Catalytic activityi

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

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionGlycosidase, Hormone, Hydrolase
LigandVitamin D

Enzyme and pathway databases

ReactomeiR-HSA-109704 PI3K Cascade
R-HSA-1257604 PIP3 activates AKT signaling
R-HSA-190374 FGFR1c and Klotho ligand binding and activation
R-HSA-2219530 Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5654219 Phospholipase C-mediated cascade: FGFR1
R-HSA-5654687 Downstream signaling of activated FGFR1
R-HSA-5654688 SHC-mediated cascade:FGFR1
R-HSA-5654689 PI-3K cascade:FGFR1
R-HSA-5654693 FRS-mediated FGFR1 signaling
R-HSA-5654726 Negative regulation of FGFR1 signaling
R-HSA-5673001 RAF/MAP kinase cascade
R-HSA-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling

Protein family/group databases

CAZyiGH1 Glycoside Hydrolase Family 1
TCDBi8.A.49.1.1 the klotho auxiliary protein (klotho) family

Names & Taxonomyi

Protein namesi
Recommended name:
Klotho (EC:3.2.1.31)
Cleaved into the following chain:
Gene namesi
Name:KL
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 13

Organism-specific databases

EuPathDBiHostDB:ENSG00000133116.7
HGNCiHGNC:6344 KL
MIMi604824 gene
neXtProtiNX_Q9UEF7

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini34 – 981ExtracellularSequence analysisAdd BLAST948
Transmembranei982 – 1002HelicalSequence analysisAdd BLAST21
Topological domaini1003 – 1012CytoplasmicSequence analysis10

Keywords - Cellular componenti

Cell membrane, Membrane, Secreted

Pathology & Biotechi

Involvement in diseasei

Tumoral calcinosis, hyperphosphatemic, familial, 3 (HFTC3)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of hyperphosphatemic tumoral calcinosis, a rare autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Some patients have recurrent, transient, painful swellings of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis and absence of skin involvement.
See also OMIM:617994
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_064554193H → R in HFTC3; impairs the ability to form a ternary complex with FGF23 and FGFR1c; impairs KL-dependent FGF23 signaling. 1 PublicationCorresponds to variant dbSNP:rs121908423EnsemblClinVar.1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi9365
MalaCardsiKL
MIMi617994 phenotype
OpenTargetsiENSG00000133116
Orphaneti306661 Familial hyperphosphatemic tumoral calcinosis/Hyperphosphatemic hyperostosis syndrome
PharmGKBiPA30130

Polymorphism and mutation databases

BioMutaiKL
DMDMi77416517

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 33Sequence analysisAdd BLAST33
ChainiPRO_000004224334 – 1012KlothoAdd BLAST979
ChainiPRO_000004224434 – ?Klotho peptideBy similarity

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi106N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi159N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi283N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi344N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi607N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi612N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi694N-linked (GlcNAc...) asparagineSequence analysis1

Post-translational modificationi

N-glycosylated.By similarity

Keywords - PTMi

Glycoprotein

Proteomic databases

PaxDbiQ9UEF7
PeptideAtlasiQ9UEF7
PRIDEiQ9UEF7
ProteomicsDBi84144
84145 [Q9UEF7-2]

PTM databases

GlyConnecti1435
iPTMnetiQ9UEF7
PhosphoSitePlusiQ9UEF7

Miscellaneous databases

PMAP-CutDBiQ9UEF7

Expressioni

Tissue specificityi

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.5 Publications

Gene expression databases

BgeeiENSG00000133116 Expressed in 149 organ(s), highest expression level in nephron tubule
CleanExiHS_KL
GenevisibleiQ9UEF7 HS

Interactioni

Subunit structurei

Homodimer. Interacts with FGF23 and FGFR1.By similarity

GO - Molecular functioni

Protein-protein interaction databases

IntActiQ9UEF7, 1 interactor
STRINGi9606.ENSP00000369442

Structurei

Secondary structure

11012
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ9UEF7
SMRiQ9UEF7
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni57 – 506Glycosyl hydrolase-1 1Add BLAST450
Regioni515 – 953Glycosyl hydrolase-1 2Add BLAST439

Domaini

Sequence similaritiesi

Keywords - Domaini

Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0626 Eukaryota
COG2723 LUCA
GeneTreeiENSGT00550000074452
HOGENOMiHOG000060126
HOVERGENiHBG081856
InParanoidiQ9UEF7
KOiK14756
OMAiYVVAWHG
OrthoDBiEOG091G0035
PhylomeDBiQ9UEF7
TreeFamiTF314803

Family and domain databases

InterProiView protein in InterPro
IPR001360 Glyco_hydro_1
IPR033132 Glyco_hydro_1_N_CS
IPR017853 Glycoside_hydrolase_SF
IPR028546 Klotho
PANTHERiPTHR10353 PTHR10353, 5 hits
PTHR10353:SF10 PTHR10353:SF10, 5 hits
PfamiView protein in Pfam
PF00232 Glyco_hydro_1, 3 hits
PRINTSiPR00131 GLHYDRLASE1
SUPFAMiSSF51445 SSF51445, 2 hits
PROSITEiView protein in PROSITE
PS00653 GLYCOSYL_HYDROL_F1_2, 1 hit

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: Q9UEF7-1) [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
MPASAPPRRP RPPPPSLSLL LVLLGLGGRR LRAEPGDGAQ TWARFSRPPA
60 70 80 90 100
PEAAGLFQGT FPDGFLWAVG SAAYQTEGGW QQHGKGASIW DTFTHHPLAP
110 120 130 140 150
PGDSRNASLP LGAPSPLQPA TGDVASDSYN NVFRDTEALR ELGVTHYRFS
160 170 180 190 200
ISWARVLPNG SAGVPNREGL RYYRRLLERL RELGVQPVVT LYHWDLPQRL
210 220 230 240 250
QDAYGGWANR ALADHFRDYA ELCFRHFGGQ VKYWITIDNP YVVAWHGYAT
260 270 280 290 300
GRLAPGIRGS PRLGYLVAHN LLLAHAKVWH LYNTSFRPTQ GGQVSIALSS
310 320 330 340 350
HWINPRRMTD HSIKECQKSL DFVLGWFAKP VFIDGDYPES MKNNLSSILP
360 370 380 390 400
DFTESEKKFI KGTADFFALC FGPTLSFQLL DPHMKFRQLE SPNLRQLLSW
410 420 430 440 450
IDLEFNHPQI FIVENGWFVS GTTKRDDAKY MYYLKKFIME TLKAIKLDGV
460 470 480 490 500
DVIGYTAWSL MDGFEWHRGY SIRRGLFYVD FLSQDKMLLP KSSALFYQKL
510 520 530 540 550
IEKNGFPPLP ENQPLEGTFP CDFAWGVVDN YIQVDTTLSQ FTDLNVYLWD
560 570 580 590 600
VHHSKRLIKV DGVVTKKRKS YCVDFAAIQP QIALLQEMHV THFRFSLDWA
610 620 630 640 650
LILPLGNQSQ VNHTILQYYR CMASELVRVN ITPVVALWQP MAPNQGLPRL
660 670 680 690 700
LARQGAWENP YTALAFAEYA RLCFQELGHH VKLWITMNEP YTRNMTYSAG
710 720 730 740 750
HNLLKAHALA WHVYNEKFRH AQNGKISIAL QADWIEPACP FSQKDKEVAE
760 770 780 790 800
RVLEFDIGWL AEPIFGSGDY PWVMRDWLNQ RNNFLLPYFT EDEKKLIQGT
810 820 830 840 850
FDFLALSHYT TILVDSEKED PIKYNDYLEV QEMTDITWLN SPSQVAVVPW
860 870 880 890 900
GLRKVLNWLK FKYGDLPMYI ISNGIDDGLH AEDDQLRVYY MQNYINEALK
910 920 930 940 950
AHILDGINLC GYFAYSFNDR TAPRFGLYRY AADQFEPKAS MKHYRKIIDS
960 970 980 990 1000
NGFPGPETLE RFCPEEFTVC TECSFFHTRK SLLAFIAFLF FASIISLSLI
1010
FYYSKKGRRS YK
Length:1,012
Mass (Da):116,181
Last modified:October 11, 2005 - v2
Checksum:i62031BD73E322E63
GO
Isoform 2 (identifier: Q9UEF7-2) [UniParc]FASTAAdd to basket
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.
Show »
Length:549
Mass (Da):62,135
Checksum:iCAD8D74DB71C49C6
GO

Polymorphismi

Homozygosity for KL-VS allele is associated with decreased longevity and increased cardiovascular disease risk.2 Publications

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02358215P → Q1 PublicationCorresponds to variant dbSNP:rs1052018Ensembl.1
Natural variantiVAR_02358345F → V1 PublicationCorresponds to variant dbSNP:rs1052019Ensembl.1
Natural variantiVAR_064554193H → R in HFTC3; impairs the ability to form a ternary complex with FGF23 and FGFR1c; impairs KL-dependent FGF23 signaling. 1 PublicationCorresponds to variant dbSNP:rs121908423EnsemblClinVar.1
Natural variantiVAR_023584352F → V in allele KL-VS; associated with S-370. 2 PublicationsCorresponds to variant dbSNP:rs9536314EnsemblClinVar.1
Natural variantiVAR_023585370C → S in allele KL-VS; associated with V-352. 2 PublicationsCorresponds to variant dbSNP:rs9527025EnsemblClinVar.1
Natural variantiVAR_049295514P → S. Corresponds to variant dbSNP:rs3752472EnsemblClinVar.1
Natural variantiVAR_036449954P → L in a colorectal cancer sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs139939367Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_015824535 – 549DTTLS…NVYLW → SQLTKPISSLTKPYH in isoform 2. 1 PublicationAdd BLAST15
Alternative sequenceiVSP_015825550 – 1012Missing in isoform 2. 1 PublicationAdd BLAST463

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB005142 mRNA Translation: BAA23382.1
AB009667 Genomic DNA Translation: BAA24940.1
AB009667 Genomic DNA Translation: BAA24941.1
AL161898 Genomic DNA No translation available.
Z92540 Genomic DNA Translation: CAC94767.1
Z84483 Genomic DNA Translation: CAC94773.1
CCDSiCCDS9347.1 [Q9UEF7-1]
PIRiJC5925
JC5926
RefSeqiNP_004786.2, NM_004795.3 [Q9UEF7-1]
UniGeneiHs.524953

Genome annotation databases

EnsembliENST00000380099; ENSP00000369442; ENSG00000133116 [Q9UEF7-1]
GeneIDi9365
KEGGihsa:9365
UCSCiuc001uus.3 human [Q9UEF7-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

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
AB005142 mRNA Translation: BAA23382.1
AB009667 Genomic DNA Translation: BAA24940.1
AB009667 Genomic DNA Translation: BAA24941.1
AL161898 Genomic DNA No translation available.
Z92540 Genomic DNA Translation: CAC94767.1
Z84483 Genomic DNA Translation: CAC94773.1
CCDSiCCDS9347.1 [Q9UEF7-1]
PIRiJC5925
JC5926
RefSeqiNP_004786.2, NM_004795.3 [Q9UEF7-1]
UniGeneiHs.524953

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5W21X-ray3.00A1-981[»]
ProteinModelPortaliQ9UEF7
SMRiQ9UEF7
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ9UEF7, 1 interactor
STRINGi9606.ENSP00000369442

Protein family/group databases

CAZyiGH1 Glycoside Hydrolase Family 1
TCDBi8.A.49.1.1 the klotho auxiliary protein (klotho) family

PTM databases

GlyConnecti1435
iPTMnetiQ9UEF7
PhosphoSitePlusiQ9UEF7

Polymorphism and mutation databases

BioMutaiKL
DMDMi77416517

Proteomic databases

PaxDbiQ9UEF7
PeptideAtlasiQ9UEF7
PRIDEiQ9UEF7
ProteomicsDBi84144
84145 [Q9UEF7-2]

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000380099; ENSP00000369442; ENSG00000133116 [Q9UEF7-1]
GeneIDi9365
KEGGihsa:9365
UCSCiuc001uus.3 human [Q9UEF7-1]

Organism-specific databases

CTDi9365
DisGeNETi9365
EuPathDBiHostDB:ENSG00000133116.7
GeneCardsiKL
H-InvDBiHIX0011224
HGNCiHGNC:6344 KL
MalaCardsiKL
MIMi604824 gene
617994 phenotype
neXtProtiNX_Q9UEF7
OpenTargetsiENSG00000133116
Orphaneti306661 Familial hyperphosphatemic tumoral calcinosis/Hyperphosphatemic hyperostosis syndrome
PharmGKBiPA30130
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0626 Eukaryota
COG2723 LUCA
GeneTreeiENSGT00550000074452
HOGENOMiHOG000060126
HOVERGENiHBG081856
InParanoidiQ9UEF7
KOiK14756
OMAiYVVAWHG
OrthoDBiEOG091G0035
PhylomeDBiQ9UEF7
TreeFamiTF314803

Enzyme and pathway databases

ReactomeiR-HSA-109704 PI3K Cascade
R-HSA-1257604 PIP3 activates AKT signaling
R-HSA-190374 FGFR1c and Klotho ligand binding and activation
R-HSA-2219530 Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5654219 Phospholipase C-mediated cascade: FGFR1
R-HSA-5654687 Downstream signaling of activated FGFR1
R-HSA-5654688 SHC-mediated cascade:FGFR1
R-HSA-5654689 PI-3K cascade:FGFR1
R-HSA-5654693 FRS-mediated FGFR1 signaling
R-HSA-5654726 Negative regulation of FGFR1 signaling
R-HSA-5673001 RAF/MAP kinase cascade
R-HSA-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling

Miscellaneous databases

GeneWikiiKlotho_(biology)
GenomeRNAii9365
PMAP-CutDBiQ9UEF7
PROiPR:Q9UEF7
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000133116 Expressed in 149 organ(s), highest expression level in nephron tubule
CleanExiHS_KL
GenevisibleiQ9UEF7 HS

Family and domain databases

InterProiView protein in InterPro
IPR001360 Glyco_hydro_1
IPR033132 Glyco_hydro_1_N_CS
IPR017853 Glycoside_hydrolase_SF
IPR028546 Klotho
PANTHERiPTHR10353 PTHR10353, 5 hits
PTHR10353:SF10 PTHR10353:SF10, 5 hits
PfamiView protein in Pfam
PF00232 Glyco_hydro_1, 3 hits
PRINTSiPR00131 GLHYDRLASE1
SUPFAMiSSF51445 SSF51445, 2 hits
PROSITEiView protein in PROSITE
PS00653 GLYCOSYL_HYDROL_F1_2, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiKLOT_HUMAN
AccessioniPrimary (citable) accession number: Q9UEF7
Secondary accession number(s): Q5VZ95
, Q96KV5, Q96KW5, Q9UEI9, Q9Y4F0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 11, 2005
Last sequence update: October 11, 2005
Last modified: November 7, 2018
This is version 152 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human chromosome 13
    Human chromosome 13: entries, gene names and cross-references to MIM
  7. Glycosyl hydrolases
    Classification of glycosyl hydrolase families and list of entries
  8. Protein Spotlight
    Protein Spotlight articles and cited UniProtKB/Swiss-Prot entries
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