The main gap we have identified in the WNT/PCP field is on mechanistic/structural studies related to full-length Vangl2. Vangl2 is a membrane-embedded protein characterized by the presence of four contiguous transmembrane helices and two cytosolic regions, a highly phosphorylated N-terminus, and a multi-domain C-terminus, which serve as a scaffold upon which the core pathway components as well as positive and negative regulators of the WNT/PCP signaling assemble. By applying state-of-the-art structural biology approaches, we first aim to gain structural insights into Vangl2 activation mechanisms by accomplishing the following: Objective 1: To express and purify Vangl2 protein for structural analysis. To achieve these goals, we collectively have extensive experience in embedding structural information in a physiologically meaningful context in order to translate the findings obtained at atomistic or molecular level to unravel the scaffolding function of the membrane protein Vangl2 in WNT/PCP signaling.