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7rpi

From Proteopedia

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Current revision

Cryo-EM structure of murine Dispatched 'T' conformation

Structural highlights

7rpi is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.5Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).^[1] ^[2] ^[3] ^[4]

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^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Caspary T, Garcia-Garcia MJ, Huangfu D, Eggenschwiler JT, Wyler MR, Rakeman AS, Alcorn HL, Anderson KV. Mouse Dispatched homolog1 is required for long-range, but not juxtacrine, Hh signaling. Curr Biol. 2002 Sep 17;12(18):1628-32. doi: 10.1016/s0960-9822(02)01147-8. PMID:12372258 doi:http://dx.doi.org/10.1016/s0960-9822(02)01147-8
↑ Ma Y, Erkner A, Gong R, Yao S, Taipale J, Basler K, Beachy PA. Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell. 2002 Oct 4;111(1):63-75. doi: 10.1016/s0092-8674(02)00977-7. PMID:12372301 doi:http://dx.doi.org/10.1016/s0092-8674(02)00977-7
↑ Kawakami T, Kawcak T, Li YJ, Zhang W, Hu Y, Chuang PT. Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling. Development. 2002 Dec;129(24):5753-65. PMID:12421714
↑ Tukachinsky H, Kuzmickas RP, Jao CY, Liu J, Salic A. Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand. Cell Rep. 2012 Aug 30;2(2):308-20. doi: 10.1016/j.celrep.2012.07.010. Epub 2012, Aug 16. PMID:22902404 doi:http://dx.doi.org/10.1016/j.celrep.2012.07.010
↑ Wang Q, Asarnow DE, Ding K, Mann RK, Hatakeyama J, Zhang Y, Ma Y, Cheng Y, Beachy PA. Dispatched uses Na(+) flux to power release of lipid-modified Hedgehog. Nature. 2021 Oct 27. pii: 10.1038/s41586-021-03996-0. doi:, 10.1038/s41586-021-03996-0. PMID:34707294 doi:http://dx.doi.org/10.1038/s41586-021-03996-0

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7rpi"

@@ Line 3: / Line 3: @@
 <StructureSection load='7rpi' size='340' side='right'caption='[[7rpi]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7rpi]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RPI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RPI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7rpi]] is a 1 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=7RPI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RPI FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</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=7rpi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rpi OCA], [https://pdbe.org/7rpi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rpi RCSB], [https://www.ebi.ac.uk/pdbsum/7rpi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rpi 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>
+[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 ==
@@ Line 23: / Line 24: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Asarnow, D]]
+[[Category: Mus musculus]]
-[[Category: Beachy, P A]]
+[[Category: Asarnow D]]
-[[Category: Cheng, Y]]
+[[Category: Beachy PA]]
-[[Category: Ding, K]]
+[[Category: Cheng Y]]
-[[Category: Wang, Q]]
+[[Category: Ding K]]
-[[Category: Hedgehog binding]]
+[[Category: Wang Q]]
-[[Category: Membrane protein]]
-[[Category: Rnd transporter]]
-[[Category: Sodium binding]]
-[[Category: Sterol sensing domain]]

7rpi

From Proteopedia

Current revision

Cryo-EM structure of murine Dispatched 'T' conformation

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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