8F6Q

CryoEM structure of designed modular protein oligomer C8-71

Summary for 8F6Q

• Entry DOI: 10.2210/pdb8f6q/pdb
• EMDB information: 28888
• Descriptor: C8-71 (1 entity in total)
• Functional Keywords: synthetic, self-assembling, oligomeric, helical repeats, de novo protein
• Biological source: synthetic construct
• Total number of polymer chains: 8
• Total formula weight: 187480.03

Authors

Redler, R.L.,Edman, N.I.,Baker, D.,Ekiert, D.,Bhabha, G. (deposition date: 2022-11-17, release date: 2023-11-29, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.6 Å)