Klotho (KL) Human Active Protein

This gene encodes a type-I membrane protein that is related to beta-glucosidases. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing and bone loss. [provided by RefSeq, Jul 2008]

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 maybe 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.7Isoform 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.