AbstractFrizzled (Fz1-10) serve as the principal cell surface receptors for Wnt signalling. Aberrant expression of Fz is associated with cancer and neurodegeneration. The N-terminal extracellular domains of Fz include Cysteine-Rich Domain (CRD), Connector, and Linker. How the palmitoleate moiety (PAM) modified Wnt bound to Fz transduces the extracellular signal across the membrane remains incomplete. Here, we report the structures of Fz4 CRD and Connector (Fz4CRD-Connector), in complex with PAM

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... modified Wnt7a peptide (PAM peptide). Fz4CRD-Connector structures reveal an open-form of dimer – a flat-shaped hydrophobic groove to accommodate one PAM peptide at the dimer interface. Interestingly, the structure of Fz7CRD bound to PAM peptide shows a dimeric closed-form – a curved-shaped hydrophobic groove at the dimer interface for one PAM peptide bound. We also reveal that Fz4Connector has extensive interactions with Fz4CRD and contributes to the Fz4 function. The studies shed insight on the development of novel strategies to modulate Fz function.