Abstract
Hedgehog (HH) signaling is essential for metazoan development. The HH ligand is secreted into the extracellular space by a cell surface protein named Dispatched-1 (DISP1). Here, we report the cryo-EM structure of human DISP1 protein. DISP1 contains 12 transmembrane helices (TMs) and two extracellular domains (ECDs). Its ECDs reveal an open state, in contrast to its structural homologues PTCH1 and NPC1, whose extracellular/luminal domains adopt a closed state. The low-resolution structure of the DISP1 complex with dual lipid-modified HH ligand reveals how the ECDs of DISP1 engage with HH ligand. Moreover, several cholesterol-like molecules are found in the TMs, implying a transport-like function of DISP1.
Highlights
Hedgehog signaling is essential for embryonic development, whereas aberrant signaling is implicated in various cancers (Briscoe & Therond, 2013; Pak & Segal, 2016; Hu & Song, 2019; Qi & Li, 2020)
Dual lipid modifications play essential roles to form the complex with HH-N binders: 1) the cholesterol modification is indispensable for HH secretion into the extracellular space by DISP1 and SCUBE2 (Creanga et al, 2012; Tukachinsky et al, 2012) and 2) the palmitate of HH-N binds to
The expression of full-length human DISP1 in human embryonic kidney (HEK) cells turned out to be insufficient for structural studies
Summary
Hedgehog signaling is essential for embryonic development, whereas aberrant signaling is implicated in various cancers (Briscoe & Therond, 2013; Pak & Segal, 2016; Hu & Song, 2019; Qi & Li, 2020). A remarkable study showed that Furin, a proprotein convertase, can cleave the loop of DISP1-ECD-I (between residues Lys279 and Arg280 of human DISP1), which promotes HH-N release and is required for the function of DISP1 in vivo (Stewart et al, 2018). This cleavage does not interfere with the interactions between HH-N and DISP1, mutations of the cleavage site block HH release. We here report the cryo-EM structures of human DISP1 and its complex with dual lipid-modified HH ligand, which reveal an open conformation adopted by ECDs for HH binding and will extend our current understanding of HH-N biogenesis
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