UniProt functional annotation for Q9UEF7



	UniProt functional annotation for Q9UEF7

UniProt code: Q9UEF7.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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). {ECO:0000250}.

Function: 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. {ECO:0000250}.

Catalytic activity: Reaction=a beta-D-glucuronoside + H2O = an alcohol + D-glucuronate; Xref=Rhea:RHEA:17633, ChEBI:CHEBI:15377, ChEBI:CHEBI:30879, ChEBI:CHEBI:58720, ChEBI:CHEBI:83411; EC=3.2.1.31;

Subunit: Homodimer. Interacts with FGF23 and FGFR1. {ECO:0000250}.

Subcellular location: [Isoform 1]: Cell membrane {ECO:0000269|PubMed:10631108, ECO:0000269|PubMed:15135068}; Single-pass type I membrane protein {ECO:0000305}. Apical cell membrane {ECO:0000250|UniProtKB:O35082}; Single-pass type I membrane protein {ECO:0000250|UniProtKB:O35082}. Note=Isoform 1 shedding leads to a soluble peptide. {ECO:0000250|UniProtKB:O35082}.

Subcellular location: [Isoform 2]: Secreted {ECO:0000269|PubMed:10631108, ECO:0000269|PubMed:15135068}.

Subcellular location: [Klotho peptide]: Secreted {ECO:0000250|UniProtKB:O35082}.

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. {ECO:0000269|PubMed:10631108, ECO:0000269|PubMed:11043382, ECO:0000269|PubMed:11162628, ECO:0000269|PubMed:15135068, ECO:0000269|PubMed:9464267}.

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.

Ptm: N-glycosylated. {ECO:0000250}.

Polymorphism: Homozygosity for KL-VS allele is associated with decreased longevity and increased cardiovascular disease risk. {ECO:0000269|PubMed:11792841, ECO:0000269|PubMed:15677572}.

Disease: Tumoral calcinosis, hyperphosphatemic, familial, 3 (HFTC3) [MIM:617994]: A form of hyperphosphatemic tumoral calcinosis, a rare autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Some patients have recurrent, transient, painful swellings of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis and absence of skin involvement. {ECO:0000269|PubMed:17710231}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: Defects in KL may be a cause of chronic renal failure complications.

Miscellaneous: [Isoform 2]: Predominates over the membrane form in all tissues examined. {ECO:0000305}.

Similarity: Belongs to the glycosyl hydrolase 1 family. Klotho subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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). {ECO:0000250}.



Function:		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. {ECO:0000250}.


Catalytic activity:		Reaction=a beta-D-glucuronoside + H2O = an alcohol + D-glucuronate; Xref=Rhea:RHEA:17633, ChEBI:CHEBI:15377, ChEBI:CHEBI:30879, ChEBI:CHEBI:58720, ChEBI:CHEBI:83411; EC=3.2.1.31;
Subunit:		Homodimer. Interacts with FGF23 and FGFR1. {ECO:0000250}.
Subcellular location:		[Isoform 1]: Cell membrane {ECO:0000269\|PubMed:10631108, ECO:0000269\|PubMed:15135068}; Single-pass type I membrane protein {ECO:0000305}. Apical cell membrane {ECO:0000250\|UniProtKB:O35082}; Single-pass type I membrane protein {ECO:0000250\|UniProtKB:O35082}. Note=Isoform 1 shedding leads to a soluble peptide. {ECO:0000250\|UniProtKB:O35082}.
Subcellular location:		[Isoform 2]: Secreted {ECO:0000269\|PubMed:10631108, ECO:0000269\|PubMed:15135068}.
Subcellular location:		[Klotho peptide]: Secreted {ECO:0000250\|UniProtKB:O35082}.
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. {ECO:0000269\|PubMed:10631108, ECO:0000269\|PubMed:11043382, ECO:0000269\|PubMed:11162628, ECO:0000269\|PubMed:15135068, ECO:0000269\|PubMed:9464267}.
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.
Ptm:		N-glycosylated. {ECO:0000250}.
Polymorphism:		Homozygosity for KL-VS allele is associated with decreased longevity and increased cardiovascular disease risk. {ECO:0000269\|PubMed:11792841, ECO:0000269\|PubMed:15677572}.
Disease:		Tumoral calcinosis, hyperphosphatemic, familial, 3 (HFTC3) [MIM:617994]: A form of hyperphosphatemic tumoral calcinosis, a rare autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Some patients have recurrent, transient, painful swellings of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis and absence of skin involvement. {ECO:0000269\|PubMed:17710231}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		Defects in KL may be a cause of chronic renal failure complications.
Miscellaneous:		[Isoform 2]: Predominates over the membrane form in all tissues examined. {ECO:0000305}.
Similarity:		Belongs to the glycosyl hydrolase 1 family. Klotho subfamily. {ECO:0000305}.