پروتئین مرتبط با کلاستو: ساختار و عملکردها

Klotho (KL) family proteins share one or two glycoside hydrolase (GH) motifs homologous to GH family 1. However, the biological significance of GH motifs in KL family proteins remains elusive. We describe here that KL-related protein (KLrP), which is composed of a single GH motif, is a cytosolic β-glucocerebrosidase (GCase, EC 3.2.1.145). We detected a neutral conduritol B epoxide (CBE)-insensitive glucosylceramide (GlcCer)-degrading activity in the cytosol fractions of human fibroblasts, rat brains, and zebrafish embryos. KL family proteins emerged as a potent candidate for the neutral GCase using a bioinformatics approach. Recombinant human KLrP, but not α-KL, β-KL, or KLPH, exhibited GCase activity with a neutral pH optimum in the presence of CBE. We solved the crystal structures of KLrP and a KLrP mutant (E165Q) in complex with glucose, which indicate that KLrP forms a (β/α)8TIM barrel structure with the double-displacement mechanism of the retaining β-glycosidase. Furthermore, knockdown of endogenous KLrP in CHOP cells using small interfering RNA (siRNA) decreased the CBE-insensitive neutral GCase activity and increased the cellular levels of GlcCer, which suggests that KLrP is involved in a novel GlcCer catabolism pathway. A KLrP D106N mutant was discovered in patients with severe Gaucher disease; however, this mutation did not affect the GCase activity of KLrP. Content: Copyright Page iv Former Editors Page v Contributors Pages xi-xii Preface Pages xiii-xiv Gerald Litwack Chapter One - Klotho-Related Protein KLrP: Structure and Functions Pages 1-16 Y. Hayashi, M. Ito Chapter Two - The FGF21 Receptor Signaling Complex: Klothoβ, FGFR1c, and Other Regulatory Interactions Pages 17-58 D.M. Kilkenny, J.V. Rocheleau Chapter Three - Klotho-Dependent Cellular Transport Regulation Pages 59-84 M. Sopjani, M. Dërmaku-Sopjani Chapter Four - Klotho and the Growth Hormone/Insulin-Like Growth Factor 1 Axis: Novel Insights into Complex Interactions Pages 85-118 T. Rubinek, D. Modan-Moses Chapter Five - Klotho Prevents Translocation of NFκB Pages 119-150 P. Buendía, R. Ramírez, P. Aljama, J. Carracedo Chapter Six - The FGF23/KLOTHO Regulatory Network and Its Roles in Human Disorders Pages 151-174 S. Kinoshita, M. Kawai Chapter Seven - MicroRNA-34a and Impaired FGF19/21 Signaling in Obesity Pages 175-196 T. Fu, J.K. Kemper Chapter Eight - The Role of Alpha-Klotho as a Universal Tumor Suppressor Pages 197-214 T. Rubinek, I. Wolf Chapter Nine - Klotho Is a Neuroprotective and Cognition-Enhancing Protein Pages 215-238 C.R. Abraham, P.C. Mullen, T. Tucker-Zhou, C.D. Chen, E. Zeldich Chapter Ten - Function and Change with Aging of α-Klotho in the Kidney Pages 239-256 K. Akasaka-Manya, H. Manya, T. Endo Chapter Eleven - αKlotho and Chronic Kidney Disease Pages 257-310 J.A. Neyra, M.C. Hu Chapter Twelve - Deficiency of Soluble α-Klotho as an Independent Cause of Uremic Cardiomyopathy Pages 311-330 J. Xie, Y.-L. Wu, C.-L. Huang Index Pages 331-338

Klotho is the latest edition of a series first published in 1943 on Vitamins and Hormones and the longest-running serial published by Academic Press. It provides up-to-date information on vitamin and hormone research spanning data from molecular biology to the clinic, with volumes focusing on a single molecule or on a disease that is related to vitamins or hormones that are interpreted broadly so that related substances, such as transmitters, cytokines, growth factors, and others can be reviewed.

• Contains contributions from experts in the field of vitamins and hormones
• Covers a vast array of subjects
• In-depth, current information at the molecular to clinical levels

Klotho is the latest edition of a series first published in 1943 on Vitamins and Hormones and the longest-running serial published by Academic Press. It provides up-to-date information on vitamin and hormone research spanning data from molecular biology to the clinic, with volumes focusing on a single molecule or on a disease that is related to vitamins or hormones that are interpreted broadly so that related substances, such as transmitters, cytokines, growth factors, and others can be reviewed. Contains contributions from experts in the field of vitamins and hormones Covers a vast array of subjects In-depth, current information at the molecular to clinical levels