3F1R

Crystal structure of FGF20 dimer

3F1R の概要

• エントリーDOI: 10.2210/pdb3f1r/pdb
• 関連するPDBエントリー: 1G82 1IHK
• 分子名称: Fibroblast growth factor 20, SULFATE ION (3 entities in total)
• 機能のキーワード: beta-trefoil fold, growth factor, polymorphism, secreted, hormone
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Secreted: Q9NP95
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 47641.70

構造登録者

Kalinina, J.,Mohammadi, M. (登録日: 2008-10-28, 公開日: 2009-07-28, 最終更新日: 2023-09-06)

主引用文献

Kalinina, J.,Byron, S.A.,Makarenkova, H.P.,Olsen, S.K.,Eliseenkova, A.V.,Larochelle, W.J.,Dhanabal, M.,Blais, S.,Ornitz, D.M.,Day, L.A.,Neubert, T.A.,Pollock, P.M.,Mohammadi, M.
Homodimerization controls the fibroblast growth factor 9 subfamily's receptor binding and heparan sulfate-dependent diffusion in the extracellular matrix
Mol.Cell.Biol., 29:4663-4678, 2009

PubMed Abstract: Uncontrolled fibroblast growth factor (FGF) signaling can lead to human diseases, necessitating multiple layers of self-regulatory control mechanisms to keep its activity in check. Herein, we demonstrate that FGF9 and FGF20 ligands undergo a reversible homodimerization, occluding their key receptor binding sites. To test the role of dimerization in ligand autoinhibition, we introduced structure-based mutations into the dimer interfaces of FGF9 and FGF20. The mutations weakened the ability of the ligands to dimerize, effectively increasing the concentrations of monomeric ligands capable of binding and activating their cognate FGF receptor in vitro and in living cells. Interestingly, the monomeric ligands exhibit reduced heparin binding, resulting in their increased radii of heparan sulfate-dependent diffusion and biologic action, as evidenced by the wider dilation area of ex vivo lung cultures in response to implanted mutant FGF9-loaded beads. Hence, our data demonstrate that homodimerization autoregulates FGF9 and FGF20's receptor binding and concentration gradients in the extracellular matrix. Our study is the first to implicate ligand dimerization as an autoregulatory mechanism for growth factor bioactivity and sets the stage for engineering modified FGF9 subfamily ligands, with desired activity for use in both basic and translational research.

PubMed: 19564416
DOI: 10.1128/MCB.01780-08

実験手法

X-RAY DIFFRACTION (2.5 Å)