Ahmed, Aamir;
Shorthouse, David;
(2025)
Predicted Functional Consequences of WNT Ligand Mutations in Colorectal Cancer.
Biophysical Journal
10.1016/j.bpj.2025.03.030.
(In press).
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Abstract
Mutations to WNT ligands in cancer are poorly understood. WNT ligands are a family of secreted proteins that trigger the activation of the WNT pathway with essential roles in cell development and carcinogenesis, particularly of the colorectal tract. Whilst the structure of WNT ligands has been elucidated, little is known about how mutations in these proteins affect colorectal cancer. Here we show that mutations in WNT ligands found in colorectal cancer show regional specificity and selectivity for particular conserved sequences. We further show that mutations in colorectal cancer are not selecting for changes in the binding affinity of the ligands to their receptor. We use clinical data to identify mutations to WNT5A as under selection and correlating with patient outcome in colorectal cancer, and by combining mutational data and folding energy calculations, elastic network modelling, and molecular dynamics simulations we show that these mutations alter its structural dynamics and flexibility. Thus we predict a novel structure-function relationship for mutations in WNT ligands in human cancers.
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