O35082 (KLOT_MOUSE) 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

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	1014 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 241 and 874, 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. Essential factor for the specific interaction between FGF23 and FGFR1. Ref.1 Ref.5 Ref.6 Ref.9 Ref.14 Ref.15 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. Ref.1 Ref.5 Ref.6 Ref.9 Ref.14 Ref.15
Catalytic activity	A beta-D-glucuronoside + H2O = D-glucuronate + an alcohol. Ref.13 Ref.14
Enzyme regulation	Inhibited by D-saccharic acid 1,4-lactone and taurocholic acid. Ref.13
Subunit structure	Homodimer. Interacts with FGF23 and FGFR1. Ref.12 Ref.15
Subcellular location	Isoform 1: Cell membrane; Single-pass type I membrane protein. Note: Isoform 1 shedding leads to a soluble peptide. Ref.1 Ref.4 Ref.8 Ref.11 Ref.12 Ref.14 Isoform 2: Secreted Ref.1 Ref.4 Ref.8 Ref.11 Ref.12 Ref.14. Klotho peptide: Secreted Ref.1 Ref.4 Ref.8 Ref.11 Ref.12 Ref.14.
Tissue specificity	Membrane-bound protein is present in distal renal tubules, inner ear, ependymal cells of brain choroid plexus, elongating spermatids and mature oocytes (at protein level). Soluble peptide is present in serum (100 pM) and cerebrospinal fluid. Expressed strongly in kidney, moderately in brain choroid plexus, and at low levels in pituitary, placenta, skeletal muscle, urinary bladder, aorta, pancreas, testis, ovary, colon, thyroid gland and adipocytes. Ref.1 Ref.2 Ref.4 Ref.7 Ref.8 Ref.11 Ref.12 Ref.14
Developmental stage	Not expressed in the embryo. Expressed in the kidney of newborns. Ref.1
Induction	Induced by 1,25-dihydroxyvitamin D3 in kidney. Down-regulated by angiotensin II and up-regulated by statins through modulation of the RhoA pathway in epithelial cells (in vitro). Isoform 1 (but not isoform 2) is up-regulated by thyroid hormone in adipocytes. Ref.7 Ref.9 Ref.10 Ref.13
Domain	Contains 2 glycosyl hydrolase 1 regions. However, the first region lacks the essential Glu active site residue at position 241, and the second one lacks the essential Glu active site residue at position 874.
Post-translational modification	N-glycosylated. Ref.12
Disruption phenotype	Mice display a syndrome resembling to human aging, with short lifespan, infertility, atherosclerosis, skin atrophy, osteoporosis and emphysema. They have various metabolic abnormalities, including increased insulin sensitivity and decreased insulin production. Mice overexpressing Kl have increased resistance to insulin and IGF1, a lifespan extended of more than 20%, and generate fewer offspring. Ref.5
Sequence similarities	Belongs to the glycosyl hydrolase 1 family. Klotho subfamily.
Biophysicochemical properties	Kinetic parameters: KM=0.249 mM for 4-methylumbelliferylglucuronide Ref.13 KM=0.251 mM for estrone 3-beta-D-glucuronide KM=0.174 mM for beta-estradiol 3-beta-D-glucuronide KM=0.251 mM for estriol 3-beta-D-glucuronide Vmax=0.62 µM/h/µg enzyme pH dependence: Optimum pH is 5.5.

Ontologies

Keywords
Cellular component	Cell membrane Membrane Secreted
Coding sequence diversity	Alternative splicing
Domain	Repeat Signal Transmembrane Transmembrane helix
Molecular function	Glycosidase 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.1. Source: MGI calcium ion homeostasis Inferred from genetic interaction PubMed 22285620. Source: MGI carbohydrate metabolic process Inferred from electronic annotation. Source: InterPro energy reserve metabolic process Inferred from mutant phenotype Ref.5. Source: MGI positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway Inferred from genetic interaction PubMed 16436388. Source: MGI positive regulation of bone mineralization Inferred from electronic annotation. Source: Compara
Cellular_component	extracellular region Inferred from sequence or structural similarity Ref.2. Source: MGI integral to membrane Inferred from sequence or structural similarity Ref.2. Source: MGI plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	beta-glucuronidase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Wnt1	P04426	2	EBI-1570828,EBI-1570911
Wnt3	P17553	4	EBI-1570828,EBI-1570853
Wnt4	P22724	2	EBI-1570828,EBI-1570945
Wnt5a	P22725	2	EBI-1570828,EBI-1570983

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: O35082-1)

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: Predominates over the secreted form by more than 10 times in all tissues examined.

Isoform 2 (identifier: O35082-2)

Also known as: Secreted;

The sequence of this isoform differs from the canonical sequence as follows:
     537-550: DTTLSQFTDPNVYL → SPLTKPSVGLLLPH
     551-1014: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 34	34	Potential
	Chain	35 – 1014	980	Klotho		PRO_0000042247
	Chain	35 – ?		Klotho peptide		PRO_0000042248
Regions
	Topological domain	35 – 982	948	Extracellular Potential
	Transmembrane	983 – 1003	21	Helical; Potential
	Topological domain	1004 – 1014	11	Cytoplasmic Potential
	Region	59 – 508	450	Glycosyl hydrolase-1 1
	Region	517 – 955	439	Glycosyl hydrolase-1 2
Amino acid modifications
	Modified residue	499	1	Phosphotyrosine Ref.16
	Glycosylation	161	1	N-linked (GlcNAc...) Potential
	Glycosylation	285	1	N-linked (GlcNAc...) Potential
	Glycosylation	346	1	N-linked (GlcNAc...) Potential
	Glycosylation	609	1	N-linked (GlcNAc...) Potential
	Glycosylation	614	1	N-linked (GlcNAc...) Potential
	Glycosylation	696	1	N-linked (GlcNAc...) Potential
Natural variations
	Alternative sequence	537 – 550	14	DTTLS…PNVYL → SPLTKPSVGLLLPH in isoform 2.		VSP_015828
	Alternative sequence	551 – 1014	464	Missing in isoform 2.		VSP_015829
Experimental info
	Sequence conflict	854	1	L → V in BAA25308. Ref.2
	Sequence conflict	948	1	K → R in BAA23381. Ref.1
	Sequence conflict	948	1	K → R in BAA25308. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (Membrane-bound) [UniParc]. Last modified July 27, 2011. Version 2. Checksum: 24BD772A1F81B8EC	FASTA	1,014	116,398
	10 20 30 40 50 60 MLARAPPRRP PRLVLLRLLL LHLLLLALRA RCLSAEPGQG AQTWARFARA PAPEAAGLLH 70 80 90 100 110 120 DTFPDGFLWA VGSAAYQTEG GWRQHGKGAS IWDTFTHHSG AAPSDSPIVV APSGAPSPPL 130 140 150 160 170 180 SSTGDVASDS YNNVYRDTEG LRELGVTHYR FSISWARVLP NGTAGTPNRE GLRYYRRLLE 190 200 210 220 230 240 RLRELGVQPV VTLYHWDLPQ RLQDTYGGWA NRALADHFRD YAELCFRHFG GQVKYWITID 250 260 270 280 290 300 NPYVVAWHGY ATGRLAPGVR GSSRLGYLVA HNLLLAHAKV WHLYNTSFRP TQGGRVSIAL 310 320 330 340 350 360 SSHWINPRRM TDYNIRECQK SLDFVLGWFA KPIFIDGDYP ESMKNNLSSL LPDFTESEKR 370 380 390 400 410 420 LIRGTADFFA LSFGPTLSFQ LLDPNMKFRQ LESPNLRQLL SWIDLEYNHP PIFIVENGWF 430 440 450 460 470 480 VSGTTKRDDA KYMYYLKKFI METLKAIRLD GVDVIGYTAW SLMDGFEWHR GYSIRRGLFY 490 500 510 520 530 540 VDFLSQDKEL LPKSSALFYQ KLIEDNGFPP LPENQPLEGT FPCDFAWGVV DNYVQVDTTL 550 560 570 580 590 600 SQFTDPNVYL WDVHHSKRLI KVDGVVAKKR KPYCVDFSAI RPQITLLREM RVTHFRFSLD 610 620 630 640 650 660 WALILPLGNQ TQVNHTVLHF YRCMISELVH ANITPVVALW QPAAPHQGLP HALAKHGAWE 670 680 690 700 710 720 NPHTALAFAD YANLCFKELG HWVNLWITMN EPNTRNMTYR AGHHLLRAHA LAWHLYDDKF 730 740 750 760 770 780 RAAQKGKISI ALQADWIEPA CPFSQNDKEV AERVLEFDIG WLAEPIFGSG DYPRVMRDWL 790 800 810 820 830 840 NQKNNFLLPY FTEDEKKLVR GSFDFLAVSH YTTILVDWEK EDPMKYNDYL EVQEMTDITW 850 860 870 880 890 900 LNSPSQVAVV PWGLRKVLNW LRFKYGDLPM YVTANGIDDD PHAEQDSLRI YYIKNYVNEA 910 920 930 940 950 960 LKAYVLDDIN LCGYFAYSLS DRSAPKSGFY RYAANQFEPK PSMKHYRKII DSNGFLGSGT 970 980 990 1000 1010 LGRFCPEEYT VCTECGFFQT RKSLLVFISF LVFTFIISLA LIFHYSKKGQ RSYK
	Isoform 2 (Secreted) [UniParc]. Checksum: E59AF8F24871BDC8	FASTA	550	62,348
	10 20 30 40 50 60 MLARAPPRRP PRLVLLRLLL LHLLLLALRA RCLSAEPGQG AQTWARFARA PAPEAAGLLH 70 80 90 100 110 120 DTFPDGFLWA VGSAAYQTEG GWRQHGKGAS IWDTFTHHSG AAPSDSPIVV APSGAPSPPL 130 140 150 160 170 180 SSTGDVASDS YNNVYRDTEG LRELGVTHYR FSISWARVLP NGTAGTPNRE GLRYYRRLLE 190 200 210 220 230 240 RLRELGVQPV VTLYHWDLPQ RLQDTYGGWA NRALADHFRD YAELCFRHFG GQVKYWITID 250 260 270 280 290 300 NPYVVAWHGY ATGRLAPGVR GSSRLGYLVA HNLLLAHAKV WHLYNTSFRP TQGGRVSIAL 310 320 330 340 350 360 SSHWINPRRM TDYNIRECQK SLDFVLGWFA KPIFIDGDYP ESMKNNLSSL LPDFTESEKR 370 380 390 400 410 420 LIRGTADFFA LSFGPTLSFQ LLDPNMKFRQ LESPNLRQLL SWIDLEYNHP PIFIVENGWF 430 440 450 460 470 480 VSGTTKRDDA KYMYYLKKFI METLKAIRLD GVDVIGYTAW SLMDGFEWHR GYSIRRGLFY 490 500 510 520 530 540 VDFLSQDKEL LPKSSALFYQ KLIEDNGFPP LPENQPLEGT FPCDFAWGVV DNYVQVSPLT 550 KPSVGLLLPH

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] (ISOFORMS 1 AND 2), FUNCTION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, SUBCELLULAR LOCATION. Tissue: Kidney.
[2]	"Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein." Shiraki-Iida T., Aizawa H., Matsumura Y., Sekine S., Iida A., Anazawa H., Nagai R., Kuro-o M., Nabeshima Y. FEBS Lett. 424:6-10(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING (ISOFORMS 1 AND 2), TISSUE SPECIFICITY.
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Brain.
[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]	"Disruption of klotho gene causes an abnormal energy homeostasis in mice." Mori K., Yahata K., Mukoyama M., Suganami T., Makino H., Nagae T., Masuzaki H., Ogawa Y., Sugawara A., Nabeshima Y., Nakao K. Biochem. Biophys. Res. Commun. 278:665-670(2000) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[6]	"Decreased insulin production and increased insulin sensitivity in the klotho mutant mouse, a novel animal model for human aging." Utsugi T., Ohno T., Ohyama Y., Uchiyama T., Saito Y., Matsumura Y., Aizawa H., Itoh H., Kurabayashi M., Kawazu S., Tomono S., Oka Y., Suga T., Kuro-o M., Nabeshima Y., Nagai R. Metabolism 49:1118-1123(2000) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[7]	"Upregulation of the klotho gene expression by thyroid hormone and during adipose differentiation in 3T3-L1 adipocytes." Mizuno I., Takahashi Y., Okimura Y., Kaji H., Chihara K. Life Sci. 68:2917-2923(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION, TISSUE SPECIFICITY.
[8]	"Expression of Klotho protein in the inner ear." Kamemori M., Ohyama Y., Kurabayashi M., Takahashi K., Nagai R., Furuya N. Hear. Res. 171:103-110(2002) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[9]	"Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system." Tsujikawa H., Kurotaki Y., Fujimori T., Fukuda K., Nabeshima Y. Mol. Endocrinol. 17:2393-2403(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INDUCTION.
[10]	"HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells." Narumiya H., Sasaki S., Kuwahara N., Irie H., Kusaba T., Kameyama H., Tamagaki K., Hatta T., Takeda K., Matsubara H. Cardiovasc. Res. 64:331-336(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[11]	"Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice." Li S.-A., Watanabe M., Yamada H., Nagai A., Kinuta M., Takei K. Cell Struct. Funct. 29:91-99(2004) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[12]	"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: CLEAVAGE, TISSUE SPECIFICITY, SUBUNIT, GLYCOSYLATION, SUBCELLULAR LOCATION.
[13]	"Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides." Tohyama O., Imura A., Iwano A., Freund J.-N., Henrissat B., Fujimori T., Nabeshima Y. J. Biol. Chem. 279:9777-9784(2004) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME ACTIVITY, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES.
[14]	"Suppression of aging in mice by the hormone Klotho." Kurosu H., Yamamoto M., Clark J.D., Pastor J.V., Nandi A., Gurnani P., McGuinness O.P., Chikuda H., Yamaguchi M., Kawaguchi H., Shimomura I., Takayama Y., Herz J., Kahn C.R., Rosenblatt K.P., Kuro-o M. Science 309:1829-1833(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, LACK OF ENZYMATIC ACTIVITY, TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[15]	"Klotho converts canonical FGF receptor into a specific receptor for FGF23." Urakawa I., Yamazaki Y., Shimada T., Iijima K., Hasegawa H., Okawa K., Fujita T., Fukumoto S., Yamashita T. Nature 444:770-774(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH FGF23 AND FGFR1.
[16]	"Qualitative and quantitative analyses of protein phosphorylation in naive and stimulated mouse synaptosomal preparations." Munton R.P., Tweedie-Cullen R., Livingstone-Zatchej M., Weinandy F., Waidelich M., Longo D., Gehrig P., Potthast F., Rutishauser D., Gerrits B., Panse C., Schlapbach R., Mansuy I.M. Mol. Cell. Proteomics 6:283-293(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-499, MASS SPECTROMETRY. Tissue: Brain cortex.
+	Additional computationally mapped references.

Web resources

Protein Spotlight

The thread of life - Issue 65 of December 2005

Cross-references

Sequence databases
EMBL GenBank DDBJ	AB005141 mRNA. Translation: BAA23381.1. AB010088 mRNA. Translation: BAA25307.1. AB010091 Genomic DNA. Translation: BAA25308.1. AB010091 Genomic DNA. Translation: BAA25309.1. BC138258 mRNA. Translation: AAI38259.1. BC138259 mRNA. Translation: AAI38260.1.
IPI	IPI00124625. IPI00653162.
RefSeq	NP_038851.2. NM_013823.2.
UniGene	Mm.6500.
3D structure databases
ProteinModelPortal	O35082.
SMR	O35082. Positions 63-508, 520-921.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-39894N.
IntAct	O35082. 4 interactions.
STRING	10090.ENSMUSP00000077899.
Protein family/group databases
CAZy	GH1. Glycoside Hydrolase Family 1.
PTM databases
PhosphoSite	O35082.
Proteomic databases
PaxDb	O35082.
PRIDE	O35082.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000078856; ENSMUSP00000077899; ENSMUSG00000058488.
GeneID	16591.
KEGG	mmu:16591.
UCSC	uc009auk.2. mouse.
Organism-specific databases
CTD	9365.
MGI	MGI:1101771. Kl.
Phylogenomic databases
eggNOG	COG2723.
GeneTree	ENSGT00550000074452.
HOGENOM	HOG000060126.
HOVERGEN	HBG081856.
InParanoid	B2RR78.
KO	K14756.
OMA	YVVAWHG.
OrthoDB	EOG444KJH.
Gene expression databases
ArrayExpress	O35082.
Bgee	O35082.
CleanEx	MM_KL.
Genevestigator	O35082.
GermOnline	ENSMUSG00000058488. Mus musculus.
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
NextBio	290141.
SOURCE	Search...

Entry information

Entry name

KLOT_MOUSE

Accession

Primary (citable) accession number: O35082
Secondary accession number(s): B2RR78, O70175, O70621

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 11, 2005
Last sequence update:	July 27, 2011
Last modified:	May 1, 2013
This is version 104 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program