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| | <StructureSection load='6e4z' size='340' side='right'caption='[[6e4z]], [[Resolution|resolution]] 2.20Å' scene=''> | | <StructureSection load='6e4z' size='340' side='right'caption='[[6e4z]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6e4z]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E4Z OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6E4Z FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6e4z]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E4Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6E4Z FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.202Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=HIP:ND1-PHOSPHONOHISTIDINE'>HIP</scene>, <scene name='pdbligand=NEP:N1-PHOSPHONOHISTIDINE'>NEP</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TYS:O-SULFO-L-TYROSINE'>TYS</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HIP:ND1-PHOSPHONOHISTIDINE'>HIP</scene>, <scene name='pdbligand=NEP:N1-PHOSPHONOHISTIDINE'>NEP</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TYS:O-SULFO-L-TYROSINE'>TYS</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6e4z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e4z OCA], [http://pdbe.org/6e4z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6e4z RCSB], [http://www.ebi.ac.uk/pdbsum/6e4z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6e4z ProSAT]</span></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=6e4z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e4z OCA], [https://pdbe.org/6e4z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6e4z RCSB], [https://www.ebi.ac.uk/pdbsum/6e4z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6e4z ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[http://omim.org/entry/603776 603776]]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref> | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.<ref>PMID:17461796</ref> <ref>PMID:18197702</ref> <ref>PMID:18660751</ref> <ref>PMID:18039658</ref> <ref>PMID:22074827</ref> <ref>PMID:22580899</ref> <ref>PMID:22493497</ref> | + | [https://www.uniprot.org/uniprot/A0A097PUG4_MOUSE A0A097PUG4_MOUSE] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6e4z" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6e4z" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Antibody 3D structures|Antibody 3D structures]] |
| | + | *[[PCSK9|PCSK9]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Kirchhofer, D K]] | + | [[Category: Mus musculus]] |
| - | [[Category: Ultsch, M H]] | + | [[Category: Kirchhofer DK]] |
| - | [[Category: Antibody]] | + | [[Category: Ultsch MH]] |
| - | [[Category: Fab complex]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Pcsk9]]
| + | |
| Structural highlights
6e4z is a 3 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.202Å |
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
A0A097PUG4_MOUSE
Publication Abstract from PubMed
Proprotein convertase subtilisin/kexin 9 (PCSK9) is a key regulator of lipid metabolism by degrading liver LDL receptors. Structural studies have provided molecular details of PCSK9 function. However, the N-terminal acidic stretch of the PCSK9 prodomain (Q31-T60) has eluded structural investigation, since it is in a disordered state. The interest in this region is intensified by the presence of human missense mutations associated with low and high LDL-c levels (E32K, D35Y, and R46L, respectively), as well as two posttranslationally modified sites, sulfated Y38 and phosphorylated S47. Herein we show that a segment within this region undergoes disorder-to-order transition. Experiments with acidic stretch-derived peptides demonstrated that the folding is centered at the segment Y38-L45, which adopts an alpha-helix as determined by NMR analysis of free peptides and by X-ray crystallography of peptides in complex with antibody 6E2 (Ab6E2). In the Fab6E2-peptide complexes, the structured region features a central 2 1/4-turn alpha-helix and encompasses up to 2/3 of the length of the acidic stretch, including the missense mutations and posttranslationally modified sites. Experiments with helix-breaking proline substitutions in peptides and in PCSK9 protein indicated that Ab6E2 specifically recognizes the helical conformation of the acidic stretch. Therefore, the observed quantitative binding of Ab6E2 to native PCSK9 from various cell lines suggests that the disorder-to-order transition is a true feature of PCSK9 and not limited to peptides. Because the helix provides a constrained spatial orientation of the missense mutations and the posttranslationally modified residues, it is probable that their biological functions take place in the context of an ordered conformational state.
Identification of a Helical Segment within the Intrinsically Disordered Region of the PCSK9 Prodomain.,Ultsch M, Li W, Eigenbrot C, Di Lello P, Lipari MT, Gerhardy S, AhYoung AP, Quinn J, Franke Y, Chen Y, Kong Beltran M, Peterson A, Kirchhofer D J Mol Biol. 2019 Mar 1;431(5):885-903. doi: 10.1016/j.jmb.2018.11.025. Epub 2019 , Jan 15. PMID:30653992[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ultsch M, Li W, Eigenbrot C, Di Lello P, Lipari MT, Gerhardy S, AhYoung AP, Quinn J, Franke Y, Chen Y, Kong Beltran M, Peterson A, Kirchhofer D. Identification of a Helical Segment within the Intrinsically Disordered Region of the PCSK9 Prodomain. J Mol Biol. 2019 Mar 1;431(5):885-903. doi: 10.1016/j.jmb.2018.11.025. Epub 2019 , Jan 15. PMID:30653992 doi:http://dx.doi.org/10.1016/j.jmb.2018.11.025
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