8F6Q

CryoEM structure of designed modular protein oligomer C8-71

8F6Q の概要

• エントリーDOI: 10.2210/pdb8f6q/pdb
• EMDBエントリー: 28888
• 分子名称: C8-71 (1 entity in total)
• 機能のキーワード: synthetic, self-assembling, oligomeric, helical repeats, de novo protein
• 由来する生物種: synthetic construct
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 187480.03

構造登録者

Redler, R.L.,Edman, N.I.,Baker, D.,Ekiert, D.,Bhabha, G. (登録日: 2022-11-17, 公開日: 2023-11-29, 最終更新日: 2024-10-16)

主引用文献

Edman, N.I.,Phal, A.,Redler, R.L.,Schlichthaerle, T.,Srivatsan, S.R.,Ehnes, D.D.,Etemadi, A.,An, S.J.,Favor, A.,Li, Z.,Praetorius, F.,Gordon, M.,Vincent, T.,Marchiano, S.,Blakely, L.,Lin, C.,Yang, W.,Coventry, B.,Hicks, D.R.,Cao, L.,Bethel, N.,Heine, P.,Murray, A.,Gerben, S.,Carter, L.,Miranda, M.,Negahdari, B.,Lee, S.,Trapnell, C.,Zheng, Y.,Murry, C.E.,Schweppe, D.K.,Freedman, B.S.,Stewart, L.,Ekiert, D.C.,Schlessinger, J.,Shendure, J.,Bhabha, G.,Ruohola-Baker, H.,Baker, D.
Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies.
Cell, 187:3726-3740.e43, 2024

PubMed Abstract: Many growth factors and cytokines signal by binding to the extracellular domains of their receptors and driving association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affect signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a de novo-designed fibroblast growth factor receptor (FGFR)-binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca release and mitogen-activated protein kinase (MAPK) pathway activation. The high specificity of the designed agonists reveals distinct roles for two FGFR splice variants in driving arterial endothelium and perivascular cell fates during early vascular development. Our designed modular assemblies should be broadly useful for unraveling the complexities of signaling in key developmental transitions and for developing future therapeutic applications.

PubMed: 38861993
DOI: 10.1016/j.cell.2024.05.025

実験手法

ELECTRON MICROSCOPY (3.6 Å)