Scientists from Yale University conducted a new study of the functions of the fibroblast growth factor FGF21 that binds and is mediated by the longevity protein beta-Klotho.
Author: Ziba Kashef
Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent Yale-led study, researchers revealed the three-dimensional structure of one of these proteins, beta-Klotho, illuminating its intricate mechanism and therapeutic potential.
The study findings, published in Nature, could have implications for therapies developed to treat a wide range of medical conditions, including diabetes, obesity, and certain cancers, the researchers said.
The Klotho family of two receptor proteins are located on the surface of cells of specific tissues. The proteins bind to a family of hormones, designated endocrine FGFs, that regulate critical metabolic processes in the liver, kidneys, and brain, among other organs. To understand how beta-Klotho works, the research team used X-ray crystallography, a technique that provides high-resolution, three-dimensional views of these proteins.
The researchers' analysis yielded several insights. First, beta-Klotho is the primary receptor that binds to FGF21, a key hormone produced upon starvation. When bound to beta-Klotho, FGF21 stimulates insulin sensitivity and glucose metabolism, causing weight loss. This new understanding of beta-Klotho and FGF21 can guide the development of therapies for conditions such as type 2 diabetes in obese patients, the researchers said.
"Like insulin, FGF21 stimulates metabolism including glucose uptake," said Joseph Schlessinger, senior author and chair of pharmacology at Yale School of Medicine. "In animals and in some clinical trials of FGF21, it shows that you can increase burning of calories without changing food intake, and we now understand how to improve the biological activity of FGF21." The authors also describe a new variant of FGF21 that has 10 times higher potency and cellular activity.
Additionally, the research team presented evidence of how a structurally-related enzyme, glycosidase, which breaks down sugars, evolved into a receptor for a hormone that lowers blood sugar — which may not be a coincidence, Schlessinger added.
Having untangled the structure of beta-Klotho, Schlessinger and his colleagues have a platform for exploring potential therapies for multiple diseases. By developing drugs that enhance the pathway, he said, researchers can target diabetes and obesity. Conversely, using agents that block the pathway, they hope to explore therapies for conditions such as liver cancer and bone diseases, among others.
"The next step will be to make better hormones, make new potent blockers, do animal studies, and move forward," Schlessinger said.
Other study authors are Sangwon Lee, Jungyuen Choi, Jyotidarsini Mohanty, Leiliane P. Sousa, Francisco Tome, Els Pardon, Jan Steyaert, Mark A. Lemmon, and Irit Lax. Schlessinger has filed a patent application for structure-based designs of novel β-Klotho agonists or antagonists. The work was supported in part by the National Institutes of Health.
Source: https://news.yale.edu/2018/01/17/secrets-longevity-protein-revealed-new-study
Structures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling | Nature
Abstract
Canonical fibroblast growth factors (FGFs) activate FGF receptors (FGFRs) through paracrine or autocrine mechanisms in a process that requires cooperation with heparan sulfate proteoglycans, which function as co-receptors for FGFR activation [1,2]. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues [3,4]. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss [5]. Endocrine FGFs signal through FGFRs in a manner that requires klothos, which are cell-surface proteins that possess tandem glycosidase domains [3,4]. Here we describe the crystal structures of free and ligand-bound β-klotho extracellular regions that reveal the molecular mechanism that underlies the specificity of FGF21 towards β-klotho and demonstrate how the FGFR is activated in a klotho-dependent manner. β-Klotho serves as a primary 'zip code'-like receptor that acts as a targeting signal for FGF21, and FGFR functions as a catalytic subunit that mediates intracellular signalling. Our structures also show how the sugar-cutting enzyme glycosidase has evolved to become a specific receptor for hormones that regulate metabolic processes, including the lowering of blood sugar levels. Finally, we describe an agonistic variant of FGF21 with enhanced biological activity and present structural insights into the potential development of therapeutic agents for diseases linked to endocrine FGFs.
