View source for 8ox8


==Cryo-EM structure of ATP8B1-CDC50A in E2P autoinhibited "open" conformation==
<StructureSection load='8ox8' size='340' side='right'caption='[[8ox8]], [[Resolution|resolution]] 2.98&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8ox8]] 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=8OX8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8OX8 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]] 2.98&#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=8ox8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ox8 OCA], [https://pdbe.org/8ox8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ox8 RCSB], [https://www.ebi.ac.uk/pdbsum/8ox8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ox8 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/AT8B1_HUMAN AT8B1_HUMAN] Progressive familial intrahepatic cholestasis type 1;Intrahepatic cholestasis of pregnancy;Benign recurrent intrahepatic cholestasis type 1. The disease is caused by variants affecting the gene represented in this entry.  The disease is caused by variants affecting the gene represented in this entry.  The disease may be caused by variants affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/AT8B1_HUMAN AT8B1_HUMAN] Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of phospholipids, in particular phosphatidylcholines (PC), from the outer to the inner leaflet of the plasma membrane (PubMed:25315773, PubMed:17948906). May participate in the establishment of the canalicular membrane integrity by ensuring asymmetric distribution of phospholipids in the canicular membrane (By similarity). Thus may have a role in the regulation of bile acids transport into the canaliculus, uptake of bile acids from intestinal contents into intestinal mucosa or both and protect hepatocytes from bile salts (By similarity). Involved in the microvillus formation in polarized epithelial cells; the function seems to be independent from its flippase activity (PubMed:20512993). Participates in correct apical membrane localization of CDC42, CFTR and SLC10A2 (PubMed:25239307, PubMed:27301931). Enables CDC42 clustering at the apical membrane during enterocyte polarization through the interaction between CDC42 polybasic region and negatively charged membrane lipids provided by ATP8B1 (By similarity). Together with TMEM30A is involved in uptake of the synthetic drug alkylphospholipid perifosine (PubMed:20510206). Required for the preservation of cochlear hair cells in the inner ear (By similarity). May act as cardiolipin transporter during inflammatory injury (By similarity).[UniProtKB:Q148W0]<ref>PMID:17948906</ref> <ref>PMID:20510206</ref> <ref>PMID:20512993</ref> <ref>PMID:25239307</ref> <ref>PMID:27301931</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 8ox8" 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]]