7rph
Cryo-EM structure of murine Dispatched 'R' conformation
Structural highlights
FunctionDISP1_MOUSE Functions in hedgehog (Hh) signaling. Regulates the release and extracellular accumulation of cholesterol-modified hedgehog proteins and is hence required for effective production of the Hh signal. Synergizes with SCUBE2 to cause an increase in SHH secretion (PubMed:22902404).[1] [2] [3] [4] Publication Abstract from PubMedThe 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. Dispatched uses Na(+) flux to power release of lipid-modified Hedgehog.,Wang Q, Asarnow DE, Ding K, Mann RK, Hatakeyama J, Zhang Y, Ma Y, Cheng Y, Beachy PA Nature. 2021 Oct 27. pii: 10.1038/s41586-021-03996-0. doi:, 10.1038/s41586-021-03996-0. PMID:34707294[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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