Significance Wnt signaling has a broad spectrum of effects on cellular physiology and diseases like cancer. Much of the specificity and regulation mechanism of the Frizzled (Fzd) family, the main receptor of the Wnt pathway, remains elusive, but exploiting the activation mechanism of Fzd is pivotal to understanding the Wnt signaling pathway. Here, by using biophysical and biochemical techniques, we identify the key conformational changes that occur as the Norrin ligand binds to Fzd4, and we show the functional implications of the involved regions. We also reveal that the linker region plays an important role in communicating ligand binding with cytoplasmic signaling. Our observations offer insight into the activation mechanism of the Fzd family and the regulation of the Wnt signaling pathway.