α-Klotho in health and diseases

Abstract

α-klotho-(α-kl) was first identified as an aging gene and later shown to be a regulator of calcium and phosphate homeostasis. α-kl is predominantly expressed in tissues that are involved in mineral homeostasis, and it encodes a 130-kDa type I glycoprotein. α-Kl was first predicted to localize to the cell surface. However, large amounts of α-Kl proteins have been detected in the intra-cellular space. In addition, the extra-cellular domain is cleaved, and secreted forms have been identified in the blood, CSF and urine. These findings suggest that α-Kl has several functions that depend on its intracellular, membrane, and extra-cellular secreted forms. In fact, the intra-cellular form of α-Kl activates Ca2+ transport from the blood to the CSF in the choroid plexus and Ca2+ re-absorption in the kidney and regulates PTH secretion in parathyroid glands by controlling the trafficking of the Na+-K+-ATPase complex to plasma membrane. On the membrane, α-Kl forms a ternary complex with FGF23 and FGFR1 and negatively regulates 1, 25(OH)2D synthesis and phosphate re-absorption in the kidney. As a down-steam event of hypervitaminosis D and hyperphosphatemia, Calpain-1 is greatly activated and is responsible for many phenotypes. Although a growing number of papers have reported the biological and clinical roles of the secreted form of α-Kl, the functions of the secreted form of α-Kl are poorly understood. The extracellular domain of α-Kl contains two internal repeats that are homologous to family 1 β-glycosidase. However, critical amino acid residues that are essential for enzyme action are replaced. Nonetheless, α-Kl was found to exhibit a subtle but specific β-glucuronidase activity. This finding suggests that the function of α-Kl may be twofold; it may act as an enzyme or as a glycoside-binding protein. The analyses of the sugar chains of α-Kl binding proteins and revealed that α-Kl functions as a glycoside-binding protein.