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.
Highlights
Wnt signalling involves a series of complex pathways and underpins developmental processes [1]
Wnt signalling can be initiated or enhanced by a variety of extracellular ligands, including Wnt and Norrin proteins, which bind to Frizzled (Fzd) receptors, and R-spondins (RSPOs), which bind to Leucine-rich repeat-containing G-protein coupled receptor (LGR) family receptors
Extracellular antagonists include Wnt inhibitory factor (WIF), secreted-Frizzled related proteins, Dickkopfs (DKKs) and Notum, each of which are diverse in structure and function
Summary
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. While the volume of structures available is considerable, numerous gaps in knowledge remain, 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. The presently available data affords considerable opportunities for structure-based drug design efforts targeting canonical Wnt signalling
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