Structures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling

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. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss. Endocrine FGFs signal through FGFRs in a manner that requires klothos, which are cell-surface proteins that possess tandem glycosidase domains. 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.

Fibroblast growth factor 21 in chronic kidney disease

“…β-klotho confers high-affinity binding to FGFRs for FGF21, and FGFR1c functions as the subunit that mediates receptor dimerization and intracellular signaling [24]. In the plasma membrane of unstimulated cells, β-klotho and FGFR1c monomers are in equilibrium with β-klotho–FGFR1c heterodimers.…”

“…In the plasma membrane of unstimulated cells, β-klotho and FGFR1c monomers are in equilibrium with β-klotho–FGFR1c heterodimers. The binding of FGF21 to β-klotho via the C-terminal tail, and the bivalent binding of the FGF21 core to two FGFR1c molecules, shifts the equilibrium towards the FGF21–FGFR1c–β-klotho complex, FGFR1c dimerization, juxtaposition of the intracellular tyrosine kinase domains, kinase activation by transphosphorylation, and eventually cell signaling [24]. The intracellular tyrosine kinase domains activate the fibroblast receptor substrate alpha (FRS2α) by phosphorylation, setting in motion the Ras/Raf/ MAPK or PI3K/AKT signaling pathways, resulting in a broad downstream gene transcription profile [22].…”

A screen forPlasmodium falciparumsporozoite surface protein binding to human hepatocyte surface receptors identifies novel host-pathogen interactions

“…It is also possible that the Pf34 – FGFR4 interaction occurs in the context of a multi-molecular complex which provides higher affinity between the host and parasite members. This possibility is supported by the fact that a co-receptor, β-klotho, contributes substantially to the binding affinity of FGFR4’s endogenous ligands [28]. We were unfortunately unable to express β-klotho in sufficient quantities to further explore this possibility.…”

The FGF metabolic axis

“…Structurally, metabolic FGFs coevolve with coreceptor KL/KLB but also acquire new structural elements that direct specific contact interactions with KL/KLB and FGFRs, thereby leading to a tethered basic triad complex and subsequent activation of intracellular kinase domains of FGFRs [5,11]. The C-terminus of the metabolic FGFs mimics the interaction mode of a sugar chain that docks into the pseudo-glycolytic pocket of KL/KLB while interacting with FGFR ectodomains through the domains that are conserved across the FGF family [5,68]. Meanwhile, the interacting KL/KLB protrudes an "arm" from the membrane-proximal glycosidase domain griping onto the FGFR ectodomain.…”