New secrets of the "longevity protein"
A detailed study of the Klotho longevity protein has provided new data that will allow the development of new treatments for various diseases, including certain types of cancer, obesity and diabetes mellitus.
A family of molecules known as Klotho proteins has intrigued researchers studying the aging process for decades. Named after the Greek goddess spinning the thread of life, these proteins are not only involved in many aspects of metabolism, but also play an important role in the mechanisms of longevity.
Studies in the late 1990s showed that mice with Klotho gene mutations suffer from conditions very similar to premature aging. They are characterized by short life expectancy, infertility, as well as the development of atherosclerosis, osteoporosis, emphysema and skin atrophy.
In a later work, it was demonstrated that overexpression of the Klotho protein-coding gene increases the lifespan of mice by affecting signaling pathways mediated by insulin and insulin-like growth factor-1.
More recently, researchers at Yale University, working under the guidance of Dr. Joseph Schlessinger, deciphered the three–dimensional structure of one of these proteins - beta-Klotho, which allowed us to shed light on the complex mechanisms of its action and therapeutic potential.
The Klotho family consists of two proteins: alpha and beta. Both receptors are localized on the cell membranes of certain tissues. They bind to molecules of endocrine fibroblast growth factors (FGF, from the English fibroblast growth factor), – hormones circulating in the bloodstream that regulate critical metabolic processes in the liver, kidneys, brain and other organs.
In order to understand the mechanisms of action of beta-Klotho, the authors used the method of X-ray crystallography, which provides a three-dimensional image of protein molecules with high resolution.
The structure of the extracellular domain of beta-Klotho protein (green) associated with FGF21 (pink) and chaperone required for crystallization (orange).
The analysis made it possible to draw a number of conclusions. Firstly, beta-Klotho is the main receptor binding to FGF21, a key hormone produced by the body in conditions of hunger. When bound to beta-Klotho, FGF21 stimulates insulin sensitivity and glucose metabolism, which leads to a decrease in body weight.
Schlessinger notes that in animal experiments and a number of FGF21 clinical studies, the possibility of stimulating calorie burning without changing the amount of food consumed has been demonstrated. The authors also describe a new variant of FGF21, which has 10 times higher activity than the original protein.
In addition, the researchers received information about how the enzyme glucosidase, which has a similar structure and breaks down carbohydrate molecules, as a result of evolution turned into a receptor for a hormone that reduces blood glucose levels, which cannot be a simple coincidence.
The authors note that the development of drugs that stimulate the described signaling pathway will help in the fight against type 2 diabetes and obesity. At the same time, its blocking agents can form the basis of new therapeutic approaches to the treatment of various diseases, including liver cancer and bone diseases.
Scientists' plans for the future include work on the synthesis of more effective forms of hormones and new powerful blockers of their action, conducting animal studies and further movement towards clinical practice.
Article by Sangwon Lee et al. Structures of beta-klotho reveal a ‘zip code'-like mechanism for endocrine FGF signaling published in the journal Nature.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on Yale University: Secrets of longevity protein revealed in new study.