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Beschreibung

Klotho (UniProt: Q9UEF7, also known as EC: 3.2.1.31) is encoded by the KL gene (Gene ID:9365) in human. Klotho is a homodimeric, highly N-glycosylated, single-pass type I membrane protein that is present in kidney, placenta, small intestine, and prostate tissue. In kidney it is predominantly present in cortical renal tubules. A soluble secreted form (isoform 2, ~ 64 kDa) is present in serum and cerebrospinal fluid. The Klotho peptide generated by cleavage of the membrane-bound isoform (Isoform 1) is considered as an anti-aging circulating hormone that is reported to extend life span by inhibiting insulin/IGF1 signaling. It also acts as a cofactor for interaction of FGF23 with FGF R1, which negatively regulates the activity of 1-alpha-hydroxylase, the rate limiting enzyme in the synthesis of 1,25(OH)2D3. Klotho is synthesized with a signal peptide (aa 1-33), which is subsequently cleaved off to generate the mature form that has an extracellular domain (aa 31-981), a short transmembrane domain (aa 982-1002), and a short cytoplasmic tail (aa 1003-1012). Deficiency of Klotho is reported to shorten life-span in animal models with a myriad of disorders associated with old age, such as arteriosclerosis, osteoporosis, and skin atrophy. Klotho deficient mice also display severe hyperphosphatemia and soft tissue calcification. On the contrary, over-expression of Klotho is shown to extend life-span in murine models by about 30% with side effects, such as mild insulin resistance and enhanced resistance to oxidative stress. Defects in KL gene has been linked to chronic renal failure complications.