Extended Data Figure 8: FGF23–FGFR1c^ecto–α-klotho^ecto–HS quaternary dimer models.

a, A 2:2:2:1 FGF23–FGFR1c^ecto–α-klotho^ecto–HS quaternary dimer in two orientations related by a 90° rotation around the horizontal axis. The dimer was constructed by superimposing FGF23 from two copies of 1:1:1 FGF23–FGFR1c^ecto–α-klotho^ecto complex onto the two FGF1 molecules in the 2:2:1 FGF1–FGFR2c–HS dimer^30,31,51,52. The dimer is held together solely by HS, which bridges two FGF23 molecules in trans. Boxed pink surface denotes the location of Ala171, Ile203 and Val221 of FGFR1c, the mutation of which impairs the ability of HS to induce 2:2:2:2 quaternary dimer formation (Fig. 5f). Boxed grey region denotes the location of Met149, Asn150 and Pro151 of FGF23, the mutation of which diminishes HS-induced quaternary dimerization (Fig. 5e, f). None of these residues has any role in 2:2:2:1 quaternary dimer formation, and hence, contrary to experimental evidence (Fig. 5), mutation of these residues should not affect HS-induced FGF23–FGFR1c^ecto–α-klotho^ecto dimerization. b, A 2:2:2:2 FGF23–FGFR1c^ecto–α-klotho^ecto–HS quaternary dimer in two orientations related by a 90° rotation around the horizontal axis. See also Fig. 5g. The dimer was constructed by superimposing FGF23 from two copies of 1:1:1 FGF23–FGFR1c^ecto–α-klotho^ecto complex onto the two FGF2 molecules in the 2:2:2 FGF2–FGFR1c–HS dimer⁴. Insets show close-up views of the secondary FGF–FGFR (top) and direct FGFR–FGFR (bottom) interfaces. Grey/pink transparent surfaces denote hydrophobic interactions. Mutation of Ala171, Ile203 and Val221 (pink) impairs the ability of HS to dimerize the FGF23–FGFR1c^ecto–α-klotho^ecto ternary complex (Fig. 5f).