Research Article

Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex

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Science  05 Oct 2018:
Vol. 362, Issue 6410, eaas8843
DOI: 10.1126/science.aas8843

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It takes two to signal

The Hedgehog (HH) signaling pathway is important in development, and excessive HH signaling is associated with cancer. Signaling occurs through the G protein–coupled receptor Smoothened. The pathway is repressed by the membrane receptor Patched-1 (PTCH1), and this inhibition is relieved when PTCH1 binds the secreted protein HH. Two recent papers have described structures of HH bound to PTCH1, but surprisingly, each described a different binding epitope on HH. Qi et al. present a cryo–electron microscopy structure that explains this apparent contradiction by showing that a single HH protein uses both of these interfaces to engage two PTCH1 receptors (see the Perspective by Sommer and Lemmon). Functional assays suggest that both interfaces must be bound for efficient signaling.

Science, this issue p. eaas8843; see also p. 26