Wnt Binding Affinity Prediction for Putative Frizzled-Type Cysteine-Rich Domains

• Published in: International journal of molecular sciences Vol. 20; no. 17; p. 4168
• Main Authors: Agostino, Mark, Pohl, Sebastian Öther-Gee
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26.08.2019; MDPI
• Subjects: Adenomatous polyposis coli; Binding energy; Binding sites; Casein; Cysteine - chemistry; cysteine-rich domain; Domains; Energy; Enzymes; Frizzled; Frizzled protein; Frizzled Receptors - chemistry; Frizzled Receptors - metabolism; Genome-wide association studies; Genomes; Glycogen; Glycogen synthase kinase 3; Glycogens; Humans; Kinases; Ligands; Lipids; Localization; Models, Molecular; Neuroblastoma; Peptides; Polyposis coli; Protein Binding; Protein Interaction Domains and Motifs; Protein Multimerization; Proteins; protein‒protein interactions; Signal Transduction; smoothened; Thermodynamics; Tumorigenesis; Wnt protein; Wnt Proteins - metabolism; Wnt signalling; protein‒protein interactions; Wnt signalling; Frizzled; cysteine-rich domain; smoothened
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20174168

Several proteins other than the frizzled receptors (Fzd) and the secreted Frizzled-related proteins (sFRP) contain Fzd-type cysteine-rich domains (CRD). We have termed these domains "putative Fzd-type CRDs", as the relevance of Wnt signalling in the majority of these is unknown; the RORs, an exception to this, are well known for mediating non-canonical Wnt signalling. In this study, we have predicted the likely binding affinity of all Wnts for all putative Fzd-type CRDs. We applied both our previously determined Wnt‒Fzd CRD binding affinity prediction model, as well as a newly devised model wherein the lipid term was forced to contribute favourably to the predicted binding energy. The results obtained from our new model indicate that certain putative Fzd CRDs are much more likely to bind Wnts, in some cases exhibiting selectivity for specific Wnts. The results of this study inform the investigation of Wnt signalling modulation beyond Fzds and sFRPs.