Klotho proteins, namesake of the Greek goddess who spun the threads of life, play a key role in the regulation of metabolism and longevity. The 3 dimensional structure of beta-Klotho was revealed by researchers at Yale University illuminating its therapeutic potential and intricate mechanism.
As published in Nature Klotho proteins have the great potential for the use in the development of therapies to treat a broad range of medical conditions which include obesity, certain cancers, and diabetes. Studies of FGF21 show that increased burning of calories occurs without changing food intake, a variant of FGF21 has 10 times higher potency and cellular activity, according to the researchers.
The Klotho family of 2 proteins are found in specific tissues located on the surface of cells within. Klotho proteins bind to the endocrine FGFs hormones which regulate the critical metabolic processes in organs which include the brain, liver, and kidneys. Using X-ray crystallography the team was able to view the Klotho proteins to get a better understanding of how it works.
Several insights were yielded by the teams analysis. The primary receptor binding to FGF21 is beta-Klotho. FGF21 is a hormone that is produced upon starvation, when bound it stimulates glucose metabolism and insulin sensitivity causing weight loss. A better understanding of this process could possibly guide researchers to the development of new treatments for conditions such as type 2 diabetes in obese patients. Additionally a structurally related enzyme called Glycosidase that breaks down sugars, evolved into a receptor for a hormone that lowers blood sugar was also observed and it suggested by the team that this just may not be a coincidence.
With the structure of beta-Klotho untangled researchers now have a new platform to explore the possibilities of therapies for multiple disease. Development of drugs that enhance the pathway researchers can target such things as diabetes and the obesity epidemic. Use of agents that will block the pathway the researchers hope to explore possible therapies for conditions such as bone disease and liver cancer among others. With the next step being to make better hormones and new potent blockers to further research and move forward.
