8FFE

Crystal structure of LRP6 E1E2 domains bound to YW210.09 Fab and engineered XWnt8 peptide

Summary for 8FFE

• Entry DOI: 10.2210/pdb8ffe/pdb
• Related: 8CTG
• EMDB information: 26989
• Descriptor: Low-density lipoprotein receptor-related protein 6, YW210.09 Fab heavy chain with engineered XWnt8 NC peptide and linker, YW210.09 Fab light chain, ... (10 entities in total)
• Functional Keywords: wnt, receptor, lrp5, lrp6, ldl receptor-like protein, ywtd b-propeller, signaling protein, signaling protein-immune system complex, signaling protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 125399.74

Authors

Jude, K.M.,Tsutsumi, N.,Waghray, D.,Garcia, K.C. (deposition date: 2022-12-08, release date: 2023-03-08, Last modification date: 2024-11-20)

Primary citation

Tsutsumi, N.,Hwang, S.,Waghray, D.,Hansen, S.,Jude, K.M.,Wang, N.,Miao, Y.,Glassman, C.R.,Caveney, N.A.,Janda, C.Y.,Hannoush, R.N.,Garcia, K.C.
Structure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for coreceptor discrimination.
Proc.Natl.Acad.Sci.USA, 120:e2218238120-e2218238120, 2023

PubMed Abstract: Wnt morphogens are critical for embryonic development and tissue regeneration. Canonical Wnts form ternary receptor complexes composed of tissue-specific Frizzled (Fzd) receptors together with the shared LRP5/6 coreceptors to initiate β-catenin signaling. The cryo-EM structure of a ternary initiation complex of an affinity-matured XWnt8-Frizzled8-LRP6 complex elucidates the basis of coreceptor discrimination by canonical Wnts by means of their N termini and linker domains that engage the LRP6 E1E2 domain funnels. Chimeric Wnts bearing modular linker "grafts" were able to transfer LRP6 domain specificity between different Wnts and enable non-canonical Wnt5a to signal through the canonical pathway. Synthetic peptides comprising the linker domain serve as Wnt-specific antagonists. The structure of the ternary complex provides a topological blueprint for the orientation and proximity of Frizzled and LRP6 within the Wnt cell surface signalosome.

PubMed: 36893265
DOI: 10.1073/pnas.2218238120

Experimental method

X-RAY DIFFRACTION (1.72 Å)