7RPJ

Dispatched uses Na + flux to power release of lipid-modified Hedgehog.

(2021) Nature 599: 320-324

• PubMed: 34707294 Search on PubMedSearch on PubMed Central
• DOI: 10.1038/s41586-021-03996-0
• Primary Citation of Related Structures:  
  7RPH, 7RPI, 7RPJ, 7RPK


• PubMed Abstract: 
  

The Dispatched protein, which is related to the NPC1 and PTCH1 cholesterol transporters ^1,2 and to H ⁺ -driven transporters of the RND family ^3,4 , enables tissue-patterning activity of the lipid-modified Hedgehog protein by releasing it from tightly -localized sites of embryonic expression ^5-10 ...

The Dispatched protein, which is related to the NPC1 and PTCH1 cholesterol transporters ^1,2 and to H ⁺ -driven transporters of the RND family ^3,4 , enables tissue-patterning activity of the lipid-modified Hedgehog protein by releasing it from tightly -localized sites of embryonic expression ^5-10 . Here we determine a cryo-electron microscopy structure of the mouse protein Dispatched homologue 1 (DISP1), revealing three Na ⁺ ions coordinated within a channel that traverses its transmembrane domain. We find that the rate of Hedgehog export is dependent on the Na ⁺ gradient across the plasma membrane. The transmembrane channel and Na ⁺ binding are disrupted in DISP1-NNN, a variant with asparagine substitutions for three intramembrane aspartate residues that each coordinate and neutralize the charge of one of the three Na ⁺ ions. DISP1-NNN and variants that disrupt single Na ⁺ sites retain binding to, but are impaired in export of the lipid-modified Hedgehog protein to the SCUBE2 acceptor. Interaction of the amino-terminal signalling domain of the Sonic hedgehog protein (ShhN) with DISP1 occurs via an extensive buried surface area and contacts with an extended furin-cleaved DISP1 arm. Variability analysis reveals that ShhN binding is restricted to one extreme of a continuous series of DISP1 conformations. The bound and unbound DISP1 conformations display distinct Na ⁺ -site occupancies, which suggests a mechanism by which transmembrane Na ⁺ flux may power extraction of the lipid-linked Hedgehog signal from the membrane. Na ⁺ -coordinating residues in DISP1 are conserved in PTCH1 and other metazoan RND family members, suggesting that Na ⁺ flux powers their conformationally driven activities.

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Organizational Affiliation: 

Departments of Urology, and Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA. pbeachy@stanford.edu.


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