Fig. 6: Fortilin occupies the binding space for TGF1-β1 that is normally occupied by TGFβRII.
From: Fortilin interacts with TGF-β1 and prevents TGF-β receptor activation
+, amino acid residues interfacing between TGF-β1 and TGFBRII; *, amino acid residues interfacing between TGF-β3 and TGFBRII; Identities, the amino acid residues of TGF-β2 and TGF-β3 that are identical to those of TGF-β1; ECS, extracellular space; PM, plasma membrane; P, phosphorylated amino acid residue; TGFβRI, TGF-β1 receptor I; TGFβRII, TGF-β1 receptor II. a Sequence alignment of TGF-β1, -β2, and -β3. Five amino acids (Arg25, His34, Tyr91, Gly93, and Arg94) of TGF-β1 (+) and 10 amino acids (Arg25, Lys31, Trp32, His34, Lys37, Tyr90, Tyr91, Gly93, Arg94, and Thr95) of TGF-β3 (*) interface with TGFβRII according to the prior co-crystallization studies. b Computational modeling of dimerized TGF-β1 and either fortilin or TGFβRII. Fortilin (green) and TGFβRII (blue) occupy the same spatial location in relation to dimerized TGF-β1 (red, chains A and B) and either fortilin or TGFβRII, but not both, can bind dimerized TGF-β1 at a given time. Fortilin and TGFβRII are depicted in an overlaid fashion. The small open circles denote arginine (Arg) residues. c Structural basis of the fortilin-TGF-β1 interaction—hydrogen bonding. Glu12, Glu138, Asp44, and Asp45 of fortilin create hydrogen bonding with Arg25, Trp30, Lys13, and Gly46 of one of the TGF-β1 molecules (chain A). d Structural basis of the fortilin-TGF-β1 interaction—hydrophobic binding surface. The hydrophobic region of the binding interface is formed by (a) Ile43, Leu47, and Ile48 of fortilin, (b) Phe43, Leu45, Val79, and Pro80 of the first TGF-β1 molecule (chain A), and (c) Ala72, Ala73, and Ala74 of the second TGF-β1 molecule (chain B). e The role of fortilin in the regulation of the TGF-β1 pathway. TGFβRII, when ligated by TGF-β1, recruits and phosphorylates TGFβRI, which in turn phosphorylates Smad2/3. Phosphorylated Smad2/3 enters the nucleus and activates TGF-β1 target genes (left panel). Fortilin binds TGF-β1 and prevents TGF-β1 from ligating and activating TGF-β1 receptors (right panel).
