The structural biology of canonical Wnt signalling

Abstract

The Wnt signalling pathways are of great importance in embryonic development and oncogenesis. Canonical and non-canonical Wnt signalling pathways are known, with the canonical (or β-catenin dependent) pathway being perhaps the best studied of these. While structural knowledge of proteins and interactions involved in canonical Wnt signalling has accumulated over the past 20 years, the pace of discovery has increased in recent years, with the structures of several key proteins and assemblies in the pathway being released. In this review, we provide a brief overview of canonical Wnt signalling, followed by a comprehensive overview of currently available X-ray, NMR and cryoEM data elaborating the structures of proteins and interactions involved in canonical Wnt signalling. While the volume of structures available is considerable, numerous gaps in knowledge remain, particularly a comprehensive understanding of the assembly of large multiprotein complexes mediating key aspects of pathway, as well as understanding the structure and activation of membrane receptors in the pathway. Nonetheless, the presently available data affords considerable opportunities for structure-based drug design efforts targeting canonical Wnt signalling.

LEVELNET to Visualise, Explore and Compare Protein-Protein Interaction Networks

“…Upon merging the nodes sharing more than 30% sequence identity, the size of the network reduces dramatically down to less than 50 nodes. This non-redundant version allows reasoning at the protein level, toward identifying the parts of the pathway that are described by structural information and the parts where such information is missing (Figure 3, compare the inset with Figure 1 from (1)). Several complexes formed in the membrane are clearly identifiable, for instance between Dickkopfs (DKKs), Kremen (KREM1) and LRP6, between R-spondins (RSPOs) and LGR family receptors, and between Wnt proteins (WNTs) and frizzled receptors (FZDs) (Figure 3, grey panel in inset, from left to right).…”

“…Next, we focused on the canonical Wnt signaling pathway, which regulates gene transcription by passing signals from the cell surface receptors to the nucleus. A large number of X-ray, NMR and cryoEM structures characterizing this pathway are available and were recently reviewed in (1). The authors provide a list of 85 PDB codes organized according to their cellular localization and role: secreted positive or negative regulators, transmembrane proteins, cytoplasmic proteins and intranuclear proteins.…”

Ciliary membrane, localised lipid modification and cilia function

“…The Wnt and Hh signalling are conjectured to have evolved with the metazoan species from a common signalling precursor pathway (Nusse & Clevers, 2017). Like the Hh signalling, the Wnt family of glycoproteins plays a critical role in determining cell proliferation, cell polarity and cell fate determination (Agostino & Pohl, 2020; MacDonald et al, 2009). Primary cilia formation moderates a distinct form of noncanonical Wnt signalling through the sequestration of Inversin (Bennett et al, 2020; Shiba et al, 2009), which also plays a critical role in Hh signalling by assisting the smoothened localisation to cilia (Zhang et al, 2019).…”

The adhesion GPCR Adgrg6 (Gpr126): Insights from the zebrafish model

“…In addition to therapeutics, chemical ligands that bind directly with the Adgrg6 protein could provide valuable tools to stabilize the receptor in an active or inactive conformation, which could facilitate isolation of the receptor in its in vivo conformation, or for the manipulation of pathway activity. Agonist and antagonist compounds are widely utilized as pharmacological tools to modulate the activity of key developmental signaling pathways, including those of the Hedgehog (Hh) and Wnt proteins, which signal via Smoothened and Frizzled family GPCRs, respectively (reviewed in Agostino & Pohl, 2020). A precedent for the translation of small molecules originally identified through developmental biological research to the clinic is the Smoothened inhibitor vismodegib, now a treatment for basal cell carcinoma (Ingham, 2018).…”