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Title | Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release. |
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Journal, issue, pages | Nat Commun, Vol. 12, Issue 1, Page 6966, Year 2021 |
Publish date | Nov 29, 2021 |
Authors | Wanqiu Li / Linlin Wang / Bradley M Wierbowski / Mo Lu / Feitong Dong / Wenchen Liu / Sisi Li / Peiyi Wang / Adrian Salic / Xin Gong / |
PubMed Abstract | The membrane protein Dispatched (Disp), which belongs to the RND family of small molecule transporters, is essential for Hedgehog (Hh) signaling, by catalyzing the extracellular release of palmitate- ...The membrane protein Dispatched (Disp), which belongs to the RND family of small molecule transporters, is essential for Hedgehog (Hh) signaling, by catalyzing the extracellular release of palmitate- and cholesterol-modified Hh ligands from producing cells. Disp function requires Furin-mediated proteolytic cleavage of its extracellular domain, but how this activates Disp remains obscure. Here, we employ cryo-electron microscopy to determine atomic structures of human Disp1 (hDisp1), before and after cleavage, and in complex with lipid-modified Sonic hedgehog (Shh) ligand. These structures, together with biochemical data, reveal that proteolytic cleavage opens the extracellular domain of hDisp1, removing steric hindrance to Shh binding. Structure-guided functional experiments demonstrate the role of hDisp1-Shh interactions in ligand release. Our results clarify the mechanisms of hDisp1 activation and Shh morphogen release, and highlight how a unique proteolytic cleavage event enabled acquisition of a protein substrate by a member of a family of small molecule transporters. |
External links | Nat Commun / PubMed:34845226 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.61 - 4.07 Å |
Structure data | EMDB-30956, PDB-7e2g: EMDB-30957, PDB-7e2h: EMDB-30958, PDB-7e2i: |
Chemicals | ChemComp-Y01: ChemComp-NAG: ChemComp-ZN: |
Source |
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Keywords | LIPID TRANSPORT / membrane protein |