8TZP

Structure of human Wnt7a bound to WLS and RECK

Summary for 8TZP

• Entry DOI: 10.2210/pdb8tzp/pdb
• EMDB information: 41765
• Descriptor: Protein Wnt-7a, Protein wntless homolog, Reversion-inducing cysteine-rich protein with Kazal motifs, ... (5 entities in total)
• Functional Keywords: signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 208968.89

Authors

Qi, X.,Hu, Q.,Li, X. (deposition date: 2023-08-27, release date: 2023-10-18, Last modification date: 2024-11-06)

Primary citation

Qi, X.,Hu, Q.,Elghobashi-Meinhardt, N.,Long, T.,Chen, H.,Li, X.
Molecular basis of Wnt biogenesis, secretion, and Wnt7-specific signaling.
Cell, 186:5028-5040.e14, 2023

PubMed Abstract: Wnt proteins are enzymatically lipidated by Porcupine (PORCN) in the ER and bind to Wntless (WLS) for intracellular transport and secretion. Mechanisms governing the transfer of these low-solubility Wnts from the ER to the extracellular space remain unclear. Through structural and functional analyses of Wnt7a, a crucial Wnt involved in central nervous system angiogenesis and blood-brain barrier maintenance, we have elucidated the principles of Wnt biogenesis and Wnt7-specific signaling. The Wnt7a-WLS complex binds to calreticulin (CALR), revealing that CALR functions as a chaperone to facilitate Wnt transfer from PORCN to WLS during Wnt biogenesis. Our structures, functional analyses, and molecular dynamics simulations demonstrate that a phospholipid in the core of Wnt-bound WLS regulates the association and dissociation between Wnt and WLS, suggesting a lipid-mediated Wnt secretion mechanism. Finally, the structure of Wnt7a bound to RECK, a cell-surface Wnt7 co-receptor, reveals how RECK engages the N-terminal domain of Wnt7a to activate Wnt7-specific signaling.

PubMed: 37852257
DOI: 10.1016/j.cell.2023.09.021

Experimental method

ELECTRON MICROSCOPY (3.23 Å)