View source for 8ox7


==Cryo-EM structure of ATP8B1-CDC50A in E2P autoinhibited "closed" conformation==
<StructureSection load='8ox7' size='340' side='right'caption='[[8ox7]], [[Resolution|resolution]] 2.56&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8ox7]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8OX7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8OX7 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]] 2.56&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=IP9:(2R)-3-{[(R)-{[(1S,2S,3R,4S,5S,6S)-2,6-DIHYDROXY-3,4,5-TRIS(PHOSPHONOOXY)CYCLOHEXYL]OXY}(HYDROXY)PHOSPHORYL]OXY}PROPANE-1,2-DIYL+DIOCTANOATE'>IP9</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PHD:ASPARTYL+PHOSPHATE'>PHD</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=8ox7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ox7 OCA], [https://pdbe.org/8ox7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ox7 RCSB], [https://www.ebi.ac.uk/pdbsum/8ox7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ox7 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CC50A_HUMAN CC50A_HUMAN] Accessory component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric distribution of phospholipids. Phospholipid translocation seems also to be implicated in vesicle formation and in uptake of lipid signaling molecules. The beta subunit may assist in binding of the phospholipid substrate. Required for the proper folding, assembly and ER to Golgi exit of the ATP8A2:TMEM30A flippase complex. ATP8A2:TMEM30A may be involved in regulation of neurite outgrowth, and, reconstituted to liposomes, predomiminantly transports phosphatidylserine (PS) and to a lesser extent phosphatidylethanolamine (PE). The ATP8A1:TMEM30A flippase complex seems to play a role in regulation of cell migration probably involving flippase-mediated translocation of phosphatidylethanolamine (PE) at the plasma membrane. Required for the formation of the ATP8A2, ATP8B1 and ATP8B2 P-type ATPAse intermediate phosphoenzymes. Involved in uptake of platelet-activating factor (PAF), synthetic drug alkylphospholipid edelfosine, and, probably in association with ATP8B1, of perifosine. Also mediate the export of alpha subunits ATP8A1, ATP8B1, ATP8B2, ATP8B4, ATP10A, ATP10B, ATP10D, ATP11A, ATP11B and ATP11C from the ER to other membrane localizations.<ref>PMID:20510206</ref> <ref>PMID:20947505</ref> <ref>PMID:20961850</ref> <ref>PMID:21289302</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Asymmetric distribution of phospholipids in eukaryotic membranes is essential for cell integrity, signaling pathways, and vesicular trafficking. P4-ATPases, also known as flippases, participate in creating and maintaining this asymmetry through active transport of phospholipids from the exoplasmic to the cytosolic leaflet. Here, we present a total of nine cryo-electron microscopy structures of the human flippase ATP8B1-CDC50A complex at 2.4 to 3.1 A overall resolution, along with functional and computational studies, addressing the autophosphorylation steps from ATP, substrate recognition and occlusion, as well as a phosphoinositide binding site. We find that the P4-ATPase transport site is occupied by water upon phosphorylation from ATP. Additionally, we identify two different autoinhibited states, a closed and an outward-open conformation. Furthermore, we identify and characterize the PI(3,4,5)P(3) binding site of ATP8B1 in an electropositive pocket between transmembrane segments 5, 7, 8, and 10. Our study also highlights the structural basis of a broad lipid specificity of ATP8B1 and adds phosphatidylinositol as a transport substrate for ATP8B1. We report a critical role of the sn-2 ester bond of glycerophospholipids in substrate recognition by ATP8B1 through conserved S403. These findings provide fundamental insights into ATP8B1 catalytic cycle and regulation, and substrate recognition in P4-ATPases.

Activation and substrate specificity of the human P4-ATPase ATP8B1.,Dieudonne T, Kummerer F, Laursen MJ, Stock C, Flygaard RK, Khalid S, Lenoir G, Lyons JA, Lindorff-Larsen K, Nissen P Nat Commun. 2023 Nov 18;14(1):7492. doi: 10.1038/s41467-023-42828-9. PMID:37980352<ref>PMID:37980352</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8ox7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Dieudonne T]]
[[Category: Juknaviciute Laursen M]]
[[Category: Khalid S]]
[[Category: Kock Flygaard R]]
[[Category: Kummerer F]]
[[Category: Lenoir G]]
[[Category: Lindorff-Larsen K]]
[[Category: Lyons JA]]
[[Category: Nissen P]]
[[Category: Stock C]]