Valerie Navarrete
A new Yale study has shown how a membrane receptor vital to human metabolism looks and functions, potentially allowing researchers to better develop drugs to address diseases as diabetes and obesity. The team’s research was published in the journal Nature on Jan. 25.
As a membrane receptor — which is a biological molecule that helps transmit cellular signals — klotho plays a significant role in receiving signals from fibroblast growth factors, which are common cellular messengers. Until now, however, scientists knew little about why or how klotho interacted with FGF21, a specific fibroblast growth factor. Researchers at the School of Medicine have determined that klotho is structurally related to sugar-cutting enzymes found in rice. Klotho recognizes molecules, such as FGF21, that look very similar to sugars in order to function.
“It is an extremely interesting biological question,” said Joseph Schlessinger, professor of pharmacology and the study’s senior author. “Endocrine fibroblast growth factors are interesting hormones that regulate a lot of interesting responses with a great potential for using them therapeutically, but we didn’t know how they worked.”
Using a technique called X-ray crystallography, the researchers found that klotho actually evolved from the enzymes found in rice into the highly specific and powerful membrane receptors in humans.
X-ray crystallography is a widely used technique for visualizing structures that are too small for ordinary microscopes to see. In this form of imaging, X-rays are directed at a molecule, and, based on the molecule’s structure, they are diffracted into various directions. A computer analyzes the diffraction patterns and produces a three-dimensional image of the molecule.
“Throughout my career, when you determine the mechanism of action through using crystal structure, a lot of new secrets are unveiled,” said Schlessinger. “This is the ultimate way of seeing how the molecules really function.”
By comparing the revealed structures to the sugar-cutting enzyme from rice, researchers began to understand how klotho recognizes FGF21. Part of the FGF21 protein looks like a sugar, which explains why klotho was able to recognize it. The crystal structure of klotho bound to FGF21 provides clear evidence of how the sugar-cutting domains of klotho, according to the study, “have been ‘repurposed’ in evolution to recognize FGF21 specifically.”
Even more fascinating is that FGF21 plays a significant role in sugar and alcohol metabolism, according to Schlessinger. The study points out that FGF21 can even help lower blood-sugar levels.
“We don’t think it is an accident,” he said. “One of the roles of the hormone is to regulate sugar metabolism. It acts in the brain to compromise the interest in getting further sugar.”
Given FGF21’s important role in regulating human metabolic processes, it is an attractive target for therapeutics looking at diabetes and obesity-related diseases. One study, published in the American Diabetes Association’s journal Diabetes, discovered that obesity can be characterized as a disease that is in a FGF21-resistant state.
Schlessinger recognizes this potential, and his lab has filed two patents relating to the discovery.
“This really unveils a secret and provides answers of how to develop new drugs,” he said. “We patented this finding and are likely going to start a drug company to utilize it.”
Many diseases either activate or block the FGF21 pathway, and, as a result, there is significant demand for commercial drugs for its regulation, according to Schlessinger.
According to the European Association for the Study of Obesity, obesity has nearly doubled since 1980.
Vikram Shaw | vikram.shaw@yale.edu