View source for 7rpk


==Cryo-EM structure of murine Dispatched in complex with Sonic hedgehog==
<StructureSection load='7rpk' size='340' side='right'caption='[[7rpk]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7rpk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RPK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RPK FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6OE:(2S)-3-{[(S)-(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-2-(HEXANOYLOXY)PROPYL+HEXANOATE'>6OE</scene>, <scene name='pdbligand=AV0:2-decyl-2-{[(4-O-alpha-D-glucopyranosyl-beta-D-glucopyranosyl)oxy]methyl}dodecyl+4-O-alpha-D-glucopyranosyl-beta-D-glucopyranoside'>AV0</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7rpk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rpk OCA], [https://pdbe.org/7rpk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rpk RCSB], [https://www.ebi.ac.uk/pdbsum/7rpk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rpk ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/DISP1_MOUSE DISP1_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).<ref>PMID:12372258</ref> <ref>PMID:12372301</ref> <ref>PMID:12421714</ref> <ref>PMID:22902404</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.

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<ref>PMID:34707294</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7rpk" style="background-color:#fffaf0;"></div>

==See Also==
*[[Sonic hedgehog 3D structures|Sonic hedgehog 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Asarnow D]]
[[Category: Beachy PA]]
[[Category: Cheng Y]]
[[Category: Ding K]]
[[Category: Wang Q]]