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α-Klotho in Health and Diseases

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Book cover Aging Mechanisms

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.

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  1. Laboratory of Molecular Life Science Foundation for Biomedical Research and Innovation, Kobe, Japan

    Yo-ichi Nabeshima

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  1. Department of Anatomy and Neurobiology, Nagasaki University School of Medicine, Nagasaki, Nagasaki, Japan

    Nozomu Mori

  2. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea (Republic of)

    Inhee Mook-Jung

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Nabeshima, Yi. (2015). α-Klotho in Health and Diseases. In: Mori, N., Mook-Jung, I. (eds) Aging Mechanisms. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55763-0_10

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