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

Qianqian Wang, Daniel E. Asarnow, Ke Ding, Randall K. Mann, Jason Hatakeyama, Yunxiao Zhang, Yong Ma, Yifan Cheng () and Philip A. Beachy ()
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Qianqian Wang: Stanford University School of Medicine
Daniel E. Asarnow: University of California
Ke Ding: Stanford University School of Medicine
Randall K. Mann: Stanford University School of Medicine
Jason Hatakeyama: Stanford University School of Medicine
Yunxiao Zhang: Stanford University School of Medicine
Yong Ma: Johns Hopkins University School of Medicine
Yifan Cheng: University of California
Philip A. Beachy: Stanford University School of Medicine

Nature, 2021, vol. 599, issue 7884, 320-324

Abstract: Abstract The Dispatched protein, which is related to the NPC1 and PTCH1 cholesterol transporters1,2 and to H+-driven transporters of the RND family3,4, enables tissue-patterning activity of the lipid-modified Hedgehog protein by releasing it from tightly -localized sites of embryonic expression5–10. 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.

Date: 2021
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DOI: 10.1038/s41586-021-03996-0

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