Challenge the routine! It's not alpha Klotho, it's FGF23

In a new study, researchers from Wenzhou Medical University in China, New York University Medical School in the United States and Southwest Medical Center of the University of Texas worked out the molecular structure of a protein called α - Klotho, and how it helps to transmit a hormone signal that delays aging The relevant research results were published online in the nature Journal on January 17, 2018, with the title of "α - Klotho is a non enzymatic molecular scaffold for FGF23 hormone signaling" The corresponding authors are professor Xiaokun Li, director of the center for collaborative innovation of biomedicine, Wenzhou Medical University, and Dr Moosa Mohammadi, Professor of Biochemistry and molecular pharmacology, New York University School of medicine The study refutes a 20-year-old hypothesis that the protein, named after the Greek goddess Klotho, who weaves the thread of life, is an important anti-aging hormone Instead, these findings attribute this function to fibroblast growth factor 23 (FGF23), and explain how α - Klotho helps FGF23 mediate its anti-aging effect Studies as early as 1997 have shown that mice lacking α - Klotho or FGF23 age prematurely after gene manipulation, including early-onset cardiovascular disease, cancer and cognitive decline By studying the structure of a group of related proteins including FGF23, its receptor protein (FGFR) and α - Klotho for the first time, the current research has overturned the mainstream view that α - Klotho alone plays a role as a longevity factor "By demonstrating that all the ways alpha Klotho should have protected the organ come from its ability to assist in FGF23 signaling, we further reveal the underlying causes of aging," Mohammadi said Our new structural data also pave the way for the design of new reagents that can activate or block FGF23 / α - Klotho signals as needed " To solve the structural mystery of anti-aging, Mohammadi and his colleagues used X-ray crystallography to analyze the atomic structure of these proteins They first induced FGF23 hormone to precipitate out of the solution together with its receptor protein (FGFR) and α - Klotho, and form a pile of crystals arranged repeatedly and orderly They then exposed the crystals to X-rays and used diffraction patterns to calculate the atomic structure of the proteins This new study provides evidence for the first time that FGF23 can signal cells only by forming a complex with alpha Klotho, its receptor and another partner in heparin sulfate solution FGF23 hormones produced by bone cells are known to travel through the bloodstream to cells in other organs, where they carry information by binding to and activating their receptors This new structure reveals how α - Klotho binds FGF23 to its receptor and has enough toughness to activate it The study also revealed how kidney disease can cause abnormal thickening of myocardial tissue Cardiac hypertrophy is the main cause of death in patients with renal tubular damage caused by diseases such as hypertension and diabetes When the damaged renal tubules are no longer able to adequately remove phosphate from the urine, FGF23 rises in an effort to control blood phosphate levels, in part by controlling vitamin D levels A popular assumption is that very high levels of FGF23 cause cardiac hypertrophy, but this theory is still controversial, because there is no α - Klotho in the heart tissue, and if FGF23 is to transmit signals, it must exist Previous studies have shown that the most known form of alpha -Klotho is fixed, that is, binding to cell surface membrane in renal tubules, parathyroid glands and certain brain regions Then the scientists learned that a part of the α - Klotho protein that extends from the cell surface, namely the extracellular domain, can be cut off and flow into the circulating body fluid, so it may reach the heart However, early evidence suggests that exfoliated α Klotho cannot be used as an auxiliary receptor for FGF23 This new study integrates these observations and confirms that circulating α - Klotho does function like its membrane binding form, allowing FGF23 to transmit signals The researchers say their findings will lead to another drug development race for kidney disease Mohammadi has confirmed that a key part of FGF23 hormone (its C-terminal tail peptide) competes with the intact FGF23 when injected into mice, thereby reducing its signaling and preventing cardiac hypertrophy In addition, they have been designing novel molecules that alter the FGF23 / abscission α - Klotho signal based on these newly discovered protein structures This study also suggests that a related protein, β - Klotho, acts as an auxiliary receptor to assist FGF21, a hormone associated with FGF23, in signaling FGF21 functions by signaling a balance between blood sugar and fatty acids, which affects diabetes and obesity.