Q9Z2Y9 (KLOT_RAT) 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

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [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 › Rattus

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 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	Cell membrane; Single-pass type I membrane protein By similarity. Note: Its shedding leads to a soluble peptide. Ref.3 Klotho peptide: Secreted By similarity Ref.3.
Tissue specificity	Present in cortical renal tubules and the parathyroid (at protein level). Strongly expressed in kidney. Expressed at low levels in brain, lung, intestine and ovaries. Ref.1 Ref.3 Ref.7
Developmental stage	Expressed faintly from E18 in the kidney. Expression increases in the kidney after 4 days of age. Ref.1
Induction	Down-regulated by angiotensin II and iron overload (at protein level). Down-regulated by acute inflammatory stress, and in models for long-term hypertension, diabetes mellitus and chronic renal failure. Ref.1 Ref.2 Ref.4 Ref.5 Ref.6
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 By similarity.
Sequence similarities	Belongs to the glycosyl hydrolase 1 family. Klotho subfamily.

Ontologies

Keywords
Cellular component	Cell membrane Membrane Secreted
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 direct assay Ref.1. Source: RGD aging Traceable author statement Ref.1. Source: RGD 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 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 electronic annotation. Source: Compara
Cellular_component	extracellular region Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW membrane Traceable author statement Ref.1. Source: RGD plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	beta-glucuronidase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

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_0000042249
	Chain	35 – ?		Klotho peptide By similarity		PRO_0000042250
Regions
	Topological domain	35 – 983	949	Extracellular Potential
	Transmembrane	984 – 1004	21	Helical; Potential
	Topological domain	1005 – 1014	10	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 By similarity
	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

Sequences

	Sequence		Length	Mass (Da)
	Q9Z2Y9 [UniParc]. Last modified May 1, 1999. Version 1. Checksum: 16F3B57581AC1DF0	FASTA	1,014	116,800
	10 20 30 40 50 60 MPARAPPRRL PRLLLLRLLS LHLLLLTLRA RCLSAEPGQG AQTWARFARP PVPEASGLLH 70 80 90 100 110 120 DTFPDGFLWA VGSAAYQTEG GWRQHGKGAS IWDTFTHHPR AIPEDSPIVM APSGAPLPPL 130 140 150 160 170 180 PSTGDVASDS 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 WRLYNTSFRP TQGGRVSIAL 310 320 330 340 350 360 GSHWITPRRM TDYHIRECQK SLDFVLGWFA KPIFIDGDYP KSMKNNLSSL LPDFTESEKR 370 380 390 400 410 420 FIRGTADFFA LSFGPTLSFQ LLDPSMKFRQ LESPSLRQLL SWIDLEYNHP QIFIVENGWF 430 440 450 460 470 480 VSGTTRRDDA KYMYYLKKFI MESLKAIRLD GVDVIGYTAW SLMDGFEWHR GYSIRRGLFY 490 500 510 520 530 540 VDFLSQDKEL LPKSSALFYQ KLIENNGFPP LPENQPLEGT FPCDFAWGVV DNYIQVDPTL 550 560 570 580 590 600 SQFTDPNVYL WDVHHSKRLI KVDGVVAKKR KPYCVDFSAI RPQITLLREM RVTHFRFSLD 610 620 630 640 650 660 WALILPLGNQ TQVNRTVLHF YRCMVSELVH ANITPVVALW QPATPHQGLP HALAKHGAWE 670 680 690 700 710 720 NPHTALAFAD YANLCFEELG HWVKFWITIN EPNSRNMTYR AGHHLLKAHA LAWHLYDDKF 730 740 750 760 770 780 RAAQKGKISI ALQVDWIEPA CPFSQKDKEV AERVLEFDVG WLAEPIFGSG DYPHVMREWL 790 800 810 820 830 840 NQKNNFLLPY FTEDEKKLIR GSFDFLALSH YTTILVDWEK EDPIKYNDYL EVQEMTDITW 850 860 870 880 890 900 LNSPNQVAVV PWGLRKALNW LRFKYGDLPM FVTANGIDDD PHAEQDSLRM YYIKNYVNEA 910 920 930 940 950 960 LKAYVLDGIN LCGYFAYSLS DRSVPKSGFY RYAANQFEPK PSIKHYRKII DNNGFLGSGT 970 980 990 1000 1010 LGRFCPEEYT VCTGCGFFQT RKSLLAFISF LVFAFVTSLA LIYYYSKKGR RRYK

References

[1]	"Molecular cloning of rat klotho cDNA: markedly decreased expression of klotho by acute inflammatory stress." Ohyama Y., Kurabayashi M., Masuda H., Nakamura T., Aihara Y., Kaname T., Suga T., Arai M., Aizawa H., Matsumura Y., Kuro-o M., Nabeshima Y., Nagai R. Biochem. Biophys. Res. Commun. 251:920-925(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, INDUCTION, DEVELOPMENTAL STAGE. Tissue: Lung.
[2]	"Downregulation of the Klotho gene in the kidney under sustained circulatory stress in rats." Aizawa H., Saito Y., Nakamura T., Inoue M., Imanari T., Ohyama Y., Matsumura Y., Masuda H., Oba S., Mise N., Kimura K., Hasegawa A., Kurabayashi M., Kuro-o M., Nabeshima Y., Nagai R. Biochem. Biophys. Res. Commun. 249:865-871(1998) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[3]	"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.
[4]	"Endothelial dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases." Nagai R., Saito Y., Ohyama Y., Aizawa H., Suga T., Nakamura T., Kurabayashi M., Kuroo M. Cell. Mol. Life Sci. 57:738-746(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[5]	"In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage." Mitani H., Ishizaka N., Aizawa T., Ohno M., Usui S., Suzuki T., Amaki T., Mori I., Nakamura Y., Sato M., Nangaku M., Hirata Y., Nagai R. Hypertension 39:838-843(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[6]	"Iron chelation and a free radical scavenger suppress angiotensin II-induced downregulation of klotho, an anti-aging gene, in rat." Saito K., Ishizaka N., Mitani H., Ohno M., Nagai R. FEBS Lett. 551:58-62(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[7]	"The parathyroid is a target organ for FGF23 in rats." Ben-Dov I.Z., Galitzer H., Lavi-Moshayoff V., Goetz R., Kuro-o M., Mohammadi M., Sirkis R., Naveh-Many T., Silver J. J. Clin. Invest. 117:4003-4008(2007) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY.
+	Additional computationally mapped references.

Web resources

Protein Spotlight

The thread of life - Issue 65 of December 2005

Cross-references

Sequence databases
EMBL GenBank DDBJ	AB017820 mRNA. Translation: BAA34740.1.
IPI	IPI00210396.
PIR	JE0333.
RefSeq	NP_112626.1. NM_031336.1.
UniGene	Rn.30061.
3D structure databases
ProteinModelPortal	Q9Z2Y9.
ModBase	Search...
Protein-protein interaction databases
STRING	10116.ENSRNOP00000001449.
Protein family/group databases
CAZy	GH1. Glycoside Hydrolase Family 1.
Proteomic databases
PaxDb	Q9Z2Y9.
PRIDE	Q9Z2Y9.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSRNOT00000001449; ENSRNOP00000001449; ENSRNOG00000001092.
GeneID	83504.
KEGG	rno:83504.
UCSC	RGD:620396. rat.
Organism-specific databases
CTD	9365.
RGD	620396. Kl.
Phylogenomic databases
eggNOG	COG2723.
GeneTree	ENSGT00550000074452.
HOGENOM	HOG000060126.
HOVERGEN	HBG081856.
InParanoid	Q9Z2Y9.
KO	K14756.
OMA	YVVAWHG.
OrthoDB	EOG444KJH.
Gene expression databases
ArrayExpress	Q9Z2Y9.
Genevestigator	Q9Z2Y9.
GermOnline	ENSRNOG00000001092. Rattus norvegicus.
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	615928.

Entry information

Entry name

KLOT_RAT

Accession

Primary (citable) accession number: Q9Z2Y9

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 11, 2005
Last sequence update:	May 1, 1999
Last modified:	May 1, 2013
This is version 98 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program