Reviewed, UniProtKB/Swiss-Prot Q9UEF7 (KLOT_HUMAN)

Names and origin

Protein names

Recommended name:
    Klotho
    EC=3.2.1.31
Cleaved into the following chain:
    1- Recommended name:
            Klotho peptide

Gene names

Name:

KL

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › 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.4 Ref.7 Ref.2 Ref.5 Ref.6
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	Defects in KL may be a cause of chronic renal failure complications. Ref.6
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
Domain	Repeat Signal Transmembrane
Ligand	Vitamin D
Molecular function	Glycosidase Hormone Hydrolase
PTM	Glycoprotein Phosphoprotein
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	aging Ref.8 Inferred from mutant phenotype. Source: UniProtKB carbohydrate metabolic process Inferred from electronic annotation. Source: InterPro fibroblast growth factor receptor signaling pathway Inferred from Experiment. Source: Reactome positive regulation of bone mineralization Inferred from mutant phenotype. Source: UniProtKB
Cellular component	extracellular space Ref.2 Traceable author statement. Source: ProtInc integral to membrane Traceable author statement. Source: UniProtKB integral to plasma membrane Ref.2 Traceable author statement. Source: ProtInc membrane fraction Ref.2 Traceable author statement. Source: ProtInc soluble fraction Ref.2 Traceable author statement. Source: ProtInc
Molecular function	beta-glucosidase activity Ref.1 Traceable author statement. Source: ProtInc beta-glucuronidase activity Inferred from electronic annotation. Source: EC cation binding Inferred from electronic annotation. Source: InterPro fibroblast growth factor binding Inferred from physical interaction. Source: UniProtKB hormone activity Inferred from electronic annotation. Source: UniProtKB-KW signal transducer activity Ref.1 Traceable author statement. 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.

Note: Isoform 1 shedding leads to a soluble peptide. Ref.4 Ref.7

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	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: dbSNP rs1052018. Ref.2		VAR_023582
	Natural variant	45	1	F → V: dbSNP rs1052019. Ref.1		VAR_023583
	Natural variant	352	1	F → V in allele KL-VS; associated with S-370. dbSNP rs9536314. Ref.8 Ref.9		VAR_023584
	Natural variant	370	1	C → S in allele KL-VS; associated with V-352. dbSNP rs9527025. Ref.8 Ref.9		VAR_023585
	Natural variant	514	1	P → S: dbSNP rs3752472.		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). 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: 9363890] [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: 9464267] [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: 15057823] [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: 10631108] [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: 11043382] [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: 11162628] [Abstract] Cited for: TISSUE SPECIFICITY, DISEASE.
[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: 15135068] [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: 11792841] [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: 15677572] [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: 16959974] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] LEU-954.
+	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.
UniGene	Hs.524953
3D structure databases
SMR	Q9UEF7. Positions 60-506.
ModBase	Search...
Protein-protein interaction databases
STRING	Q9UEF7.
Protein family/group databases
CAZy	GH1. Glycoside Hydrolase Family 1.
PTM databases
PhosphoSite	Q9UEF7.
Proteomic databases
PRIDE	Q9UEF7.
Genome annotation databases
Ensembl	ENST00000380099; ENSP00000369442; ENSG00000133116; Homo sapiens. [Genome view]
GeneID	9365.
KEGG	hsa:9365.
UCSC	uc001uus.1. human.
Organism-specific databases
CTD	9365.
GeneCards	GC13P032488.
H-InvDB	HIX0011224.
HGNC	HGNC:6344. KL.
HPA	HPA023480.
MIM	604824. gene+phenotype.
Orphanet	53715. Calcinosis, tumoral.
PharmGKB	PA134971572.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG11485.
HOGENOM	HBG443600.
HOVERGEN	Q9UEF7.
InParanoid	Q9UEF7.
OMA	YVVAWHG.
OrthoDB	EOG91G5QB.
PhylomeDB	Q9UEF7.
Enzyme and pathway databases
BRENDA	3.2.1.31. 247.
Reactome	REACT_9470. Signaling by FGFR.
Gene expression databases
ArrayExpress	Q9UEF7.
Bgee	Q9UEF7.
CleanEx	HS_KL.
Genevestigator	Q9UEF7.
GermOnline	ENSG00000133116. Homo sapiens.
Family and domain databases
InterPro	IPR001360. Glyco_hydro_1. IPR018120. Glyco_hydro_1_AS. IPR017853. Glyco_hydro_catalytic_core. IPR013781. Glyco_hydro_sg_catalytic. [Graphical view]
Gene3D	G3DSA:3.20.20.80. Glyco_hydro_cat. 2 hits.
PANTHER	PTHR10353. Glyco_hydro_1. 1 hit.
Pfam	PF00232. Glyco_hydro_1. 3 hits. [Graphical view]
PRINTS	PR00131. GLHYDRLASE1.
PROSITE	PS00572. GLYCOSYL_HYDROL_F1_1. False negative. PS00653. GLYCOSYL_HYDROL_F1_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
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:	January 19, 2010
This is version 72 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.