Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
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+phenotype
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 (HFTC)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:211900
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_064554193H → R in HFTC; 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
MIMi211900 phenotype
604824 gene+phenotype
OpenTargetsiENSG00000133116
Orphaneti306661 Familial tumoral calcinosis
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

PTM databases

iPTMnetiQ9UEF7
PhosphoSitePlusiQ9UEF7

Miscellaneous databases

PMAP-CutDBQ9UEF7

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
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
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Turni35 – 40Combined sources6
Helixi41 – 44Combined sources4
Helixi51 – 55Combined sources5
Beta strandi66 – 70Combined sources5
Turni74 – 77Combined sources4
Helixi89 – 95Combined sources7
Helixi133 – 142Combined sources10
Beta strandi145 – 150Combined sources6
Helixi153 – 156Combined sources4
Helixi167 – 183Combined sources17
Beta strandi186 – 194Combined sources9
Helixi199 – 202Combined sources4
Helixi206 – 208Combined sources3
Helixi212 – 226Combined sources15
Helixi227 – 229Combined sources3
Beta strandi233 – 238Combined sources6
Helixi240 – 248Combined sources9
Beta strandi253 – 255Combined sources3
Helixi261 – 283Combined sources23
Turni284 – 286Combined sources3
Helixi287 – 290Combined sources4
Beta strandi293 – 299Combined sources7
Beta strandi302 – 304Combined sources3
Beta strandi306 – 308Combined sources3
Helixi310 – 323Combined sources14
Helixi325 – 332Combined sources8
Beta strandi333 – 336Combined sources4
Helixi339 – 344Combined sources6
Beta strandi346 – 349Combined sources4
Helixi354 – 360Combined sources7
Beta strandi365 – 370Combined sources6
Helixi375 – 379Combined sources5
Helixi383 – 385Combined sources3
Beta strandi389 – 391Combined sources3
Helixi395 – 404Combined sources10
Beta strandi410 – 414Combined sources5
Helixi428 – 446Combined sources19
Beta strandi452 – 458Combined sources7
Helixi466 – 468Combined sources3
Beta strandi471 – 473Combined sources3
Beta strandi476 – 478Combined sources3
Beta strandi483 – 485Combined sources3
Helixi492 – 503Combined sources12
Helixi510 – 512Combined sources3
Beta strandi524 – 529Combined sources6
Beta strandi539 – 541Combined sources3
Beta strandi546 – 549Combined sources4
Beta strandi552 – 554Combined sources3
Beta strandi557 – 559Combined sources3
Helixi578 – 587Combined sources10
Beta strandi591 – 596Combined sources6
Helixi599 – 602Combined sources4
Beta strandi606 – 610Combined sources5
Helixi613 – 628Combined sources16
Beta strandi632 – 638Combined sources7
Turni642 – 646Combined sources5
Helixi649 – 653Combined sources5
Helixi656 – 658Combined sources3
Helixi661 – 676Combined sources16
Helixi677 – 679Combined sources3
Beta strandi683 – 689Combined sources7
Turni692 – 694Combined sources3
Helixi697 – 717Combined sources21
Turni718 – 721Combined sources4
Beta strandi725 – 731Combined sources7
Beta strandi734 – 739Combined sources6
Helixi743 – 756Combined sources14
Helixi758 – 765Combined sources8
Beta strandi766 – 769Combined sources4
Helixi772 – 780Combined sources9
Helixi791 – 797Combined sources7
Beta strandi802 – 807Combined sources6
Beta strandi811 – 817Combined sources7
Helixi821 – 823Combined sources3
Turni826 – 829Combined sources4
Beta strandi830 – 833Combined sources4
Helixi849 – 863Combined sources15
Beta strandi868 – 873Combined sources6
Helixi884 – 903Combined sources20
Beta strandi909 – 915Combined sources7
Turni919 – 921Combined sources3
Turni923 – 925Combined sources3
Beta strandi927 – 933Combined sources7
Beta strandi935 – 937Combined sources3
Helixi939 – 950Combined sources12

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...

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
OMAiYYLKKFI
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, 6 hits
PTHR10353:SF10 PTHR10353:SF10, 6 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 HFTC; 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

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: April 25, 2018
This is version 147 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

Cookie policy

We would like to use anonymized google analytics cookies to gather statistics on how uniprot.org is used in aggregate. Learn more

UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health