Structures of Β-Klotho Reveal a 'zip Code'-Like Mechanism for Endocrine FGF Signalling.

Crystal structures of free and ligand-bound β-klotho reveal that it acts as a primary receptor for FGF21, and demonstrate how a sugar-cutting enzyme has evolved to become a receptor for hormones that regulate metabolic processes. The endocrine fibroblast growth factors (FGF19, FGF21 and FGF23) are circulating hormones that regulate important metabolic and physiological functions in vertebrates. Canonical FGFs require heparan sulfate proteoglycans to activate FGF receptors, but endocrine FGFs instead depend on klotho proteins for this process. There are two klothos, encoded by different genes: β-klotho is essential for FGF19- and FGF21-dependent signaling, whereas α-klotho is required for FGF23-dependent signalling. In this issue, Joseph Schlessinger and colleagues report crystal structures of the β-klotho extracellular domain, in ligand-free form and bound to a C-terminal peptide of FGF21. Moosa Mohammadi and colleagues report the atomic structure of a 1:1:1 ternary complex, which consists of the extracellular domain that is shed from membrane-anchored α-klotho into body fluids, the FGFR1c ligand-binding domain and FGF23. These hormones and their receptors are highly desirable drug targets owing to their central role in metabolism and physiology. Their structures offer the first glimpse of klotho and provide long-awaited mechanistic insights into the signalling pathways that are regulated by endocrine FGFs. 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 activation1,2. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues3,4. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss5. Endocrine FGFs signal through FGFRs in a manner that requires klothos, which are cell-surface proteins that possess tandem glycosidase domains3,4. 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.