Q9UEF7 (KLOT_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Klotho
EC=3.2.1.31

Cleaved into the following chain:

1. Klotho peptide

Gene names

Name:

KL

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1012 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 may be 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 component	Cell membrane Membrane Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Repeat Signal Transmembrane Transmembrane helix
Ligand	Vitamin D
Molecular function	Glycosidase Hormone Hydrolase
PTM	Glycoprotein Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	acute inflammatory response Inferred from electronic annotation. Source: Compara aging Inferred from mutant phenotype Ref.8. Source: UniProtKB calcium ion homeostasis Inferred from electronic annotation. Source: Compara carbohydrate metabolic process Inferred from electronic annotation. Source: InterPro energy reserve metabolic process Inferred from electronic annotation. Source: Compara fibroblast growth factor receptor signaling pathway Traceable author statement. Source: Reactome insulin receptor signaling pathway Traceable author statement. Source: Reactome positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of bone mineralization Inferred from mutant phenotype PubMed 12110410. Source: UniProtKB
Cellular_component	extracellular region Traceable author statement. Source: Reactome extracellular space Traceable author statement Ref.8. Source: UniProtKB integral to membrane Traceable author statement Ref.8. Source: UniProtKB integral to plasma membrane Traceable author statement Ref.2. Source: ProtInc
Molecular_function	beta-glucosidase activity Traceable author statement Ref.1. Source: ProtInc beta-glucuronidase activity Inferred from electronic annotation. Source: EC 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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 33	33	Potential
	Chain	34 – 1012	979	Klotho		PRO_0000042243
	Chain	34 – ?		Klotho peptide By similarity		PRO_0000042244
Regions
	Topological domain	34 – 981	948	Extracellular Potential
	Transmembrane	982 – 1002	21	Helical; Potential
	Topological domain	1003 – 1012	10	Cytoplasmic Potential
	Region	57 – 506	450	Glycosyl hydrolase-1 1
	Region	515 – 953	439	Glycosyl hydrolase-1 2
Amino acid modifications
	Modified residue	497	1	Phosphotyrosine By similarity
	Glycosylation	106	1	N-linked (GlcNAc...) Potential
	Glycosylation	159	1	N-linked (GlcNAc...) Potential
	Glycosylation	283	1	N-linked (GlcNAc...) Potential
	Glycosylation	344	1	N-linked (GlcNAc...) Potential
	Glycosylation	607	1	N-linked (GlcNAc...) Potential
	Glycosylation	612	1	N-linked (GlcNAc...) Potential
	Glycosylation	694	1	N-linked (GlcNAc...) Potential
Natural variations
	Alternative sequence	535 – 549	15	DTTLS…NVYLW → SQLTKPISSLTKPYH in isoform 2.		VSP_015824
	Alternative sequence	550 – 1012	463	Missing in isoform 2.		VSP_015825
	Natural variant	15	1	P → Q. Ref.2 Corresponds to variant rs1052018 [ dbSNP | Ensembl ].		VAR_023582
	Natural variant	45	1	F → V. Ref.1 Corresponds to variant rs1052019 [ dbSNP | Ensembl ].		VAR_023583
	Natural variant	193	1	H → 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 variant	352	1	F → V in allele KL-VS; associated with S-370. Ref.8 Ref.9 Corresponds to variant rs9536314 [ dbSNP | Ensembl ].		VAR_023584
	Natural variant	370	1	C → S in allele KL-VS; associated with V-352. Ref.8 Ref.9 Corresponds to variant rs9527025 [ dbSNP | Ensembl ].		VAR_023585
	Natural variant	514	1	P → S. Corresponds to variant rs3752472 [ dbSNP | Ensembl ].		VAR_049295
	Natural variant	954	1	P → L in a colorectal cancer sample; somatic mutation. Ref.10		VAR_036449

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (Membrane-bound) [UniParc]. Last modified October 11, 2005. Version 2. Checksum: 62031BD73E322E63	FASTA	1,012	116,181
	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
	Isoform 2 (Secreted) [UniParc]. Checksum: CAD8D74DB71C49C6	FASTA	549	62,135
	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 YIQVSQLTKP ISSLTKPYH

References

	« Hide 'large scale' referencesShow '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. , 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. , 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.
IPI	IPI00170818. IPI00295265.
PIR	JC5925. JC5926.
RefSeq	NP_004786.2. NM_004795.3.
UniGene	Hs.524953.
3D structure databases
ProteinModelPortal	Q9UEF7.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9UEF7. 1 interaction.
STRING	9606.ENSP00000369442.
Protein family/group databases
CAZy	GH1. Glycoside Hydrolase Family 1.
PTM databases
PhosphoSite	Q9UEF7.
Polymorphism databases
DMDM	77416517.
Proteomic databases
PaxDb	Q9UEF7.
PRIDE	Q9UEF7.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000380099; ENSP00000369442; ENSG00000133116.
GeneID	9365.
KEGG	hsa:9365.
UCSC	uc001uus.3. human.
Organism-specific databases
CTD	9365.
GeneCards	GC13P033590.
H-InvDB	HIX0011224.
HGNC	HGNC:6344. KL.
HPA	HPA023480.
MIM	211900. phenotype. 604824. gene+phenotype.
neXtProt	NX_Q9UEF7.
Orphanet	53715. Tumoral calcinosis.
PharmGKB	PA30130.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG2723.
HOGENOM	HOG000060126.
HOVERGEN	HBG081856.
InParanoid	Q9UEF7.
KO	K14756.
OMA	YVVAWHG.
OrthoDB	EOG444KJH.
PhylomeDB	Q9UEF7.
Enzyme and pathway databases
Reactome	REACT_111102. Signal Transduction. REACT_116125. Disease. REACT_6900. Immune System.
Gene expression databases
ArrayExpress	Q9UEF7.
Bgee	Q9UEF7.
CleanEx	HS_KL.
Genevestigator	Q9UEF7.
GermOnline	ENSG00000133116. Homo sapiens.
Family and domain databases
Gene3D	3.20.20.80. 2 hits.
InterPro	IPR001360. Glyco_hydro_1. IPR018120. Glyco_hydro_1_AS. IPR013781. Glyco_hydro_catalytic_dom. IPR017853. Glycoside_hydrolase_SF. [Graphical view]
PANTHER	PTHR10353. PTHR10353. 1 hit.
Pfam	PF00232. Glyco_hydro_1. 3 hits. [Graphical view]
PRINTS	PR00131. GLHYDRLASE1.
SUPFAM	SSF51445. Glyco_hydro_cat. 2 hits.
PROSITE	PS00572. GLYCOSYL_HYDROL_F1_1. False negative. PS00653. GLYCOSYL_HYDROL_F1_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	9365.
NextBio	35073.
PMAP-CutDB	Q9UEF7.
SOURCE	Search...

Entry information

Entry name

KLOT_HUMAN

Accession

Primary (citable) accession number: Q9UEF7
Secondary accession number(s): Q5VZ95 , Q96KV5, Q96KW5, Q9UEI9, Q9Y4F0

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 11, 2005
Last sequence update:	October 11, 2005
Last modified:	May 1, 2013
This is version 102 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.