8frr: Difference between revisions
New page: '''Unreleased structure''' The entry 8frr is ON HOLD Authors: Ma, M.T., Lieberman, R.L., Huard, D.J.E. Description: Wild-type myocilin olfactomedin domain [[Category: Unreleased Struct... |
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==Wild-type myocilin olfactomedin domain== | |||
<StructureSection load='8frr' size='340' side='right'caption='[[8frr]], [[Resolution|resolution]] 1.27Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8frr]] is a 1 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=8FRR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FRR FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.27Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=8frr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8frr OCA], [https://pdbe.org/8frr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8frr RCSB], [https://www.ebi.ac.uk/pdbsum/8frr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8frr ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Studies of folded-to-misfolded transitions using model protein systems reveal a range of unfolding needed for exposure of amyloid-prone regions for subsequent fibrillization. Here, we probe the relationship between unfolding and aggregation for glaucoma-associated myocilin. Mutations within the olfactomedin domain of myocilin (OLF) cause a gain-of-function, namely cytotoxic intracellular aggregation, which hastens disease progression. Aggregation by wild-type OLF (OLF(WT)) competes with its chemical unfolding, but only below the threshold where OLF loses tertiary structure. Representative moderate (OLF(D380A)) and severe (OLF(I499F)) disease variants aggregate differently, with rates comparable to OLF(WT) in initial stages of unfolding, and variants adopt distinct partially folded structures seen along the OLF(WT) urea-unfolding pathway. Whether initiated with mutation or chemical perturbation, unfolding propagates outward to the propeller surface. In sum, for this large protein prone to amyloid formation, the requirement for a conformational change to promote amyloid fibrillization leads to direct competition between unfolding and aggregation. | |||
Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming beta-propeller.,Saccuzzo EG, Mebrat MD, Scelsi HF, Kim M, Ma MT, Su X, Hill SE, Rheaume E, Li R, Torres MP, Gumbart JC, Van Horn WD, Lieberman RL Nat Commun. 2024 Jan 2;15(1):155. doi: 10.1038/s41467-023-44479-2. PMID:38168102<ref>PMID:38168102</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 8frr" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: Ma | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Huard DJE]] | |||
[[Category: Lieberman RL]] | |||
[[Category: Ma MT]] | |||
Latest revision as of 12:51, 9 October 2024
Wild-type myocilin olfactomedin domainWild-type myocilin olfactomedin domain
Structural highlights
Publication Abstract from PubMedStudies of folded-to-misfolded transitions using model protein systems reveal a range of unfolding needed for exposure of amyloid-prone regions for subsequent fibrillization. Here, we probe the relationship between unfolding and aggregation for glaucoma-associated myocilin. Mutations within the olfactomedin domain of myocilin (OLF) cause a gain-of-function, namely cytotoxic intracellular aggregation, which hastens disease progression. Aggregation by wild-type OLF (OLF(WT)) competes with its chemical unfolding, but only below the threshold where OLF loses tertiary structure. Representative moderate (OLF(D380A)) and severe (OLF(I499F)) disease variants aggregate differently, with rates comparable to OLF(WT) in initial stages of unfolding, and variants adopt distinct partially folded structures seen along the OLF(WT) urea-unfolding pathway. Whether initiated with mutation or chemical perturbation, unfolding propagates outward to the propeller surface. In sum, for this large protein prone to amyloid formation, the requirement for a conformational change to promote amyloid fibrillization leads to direct competition between unfolding and aggregation. Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming beta-propeller.,Saccuzzo EG, Mebrat MD, Scelsi HF, Kim M, Ma MT, Su X, Hill SE, Rheaume E, Li R, Torres MP, Gumbart JC, Van Horn WD, Lieberman RL Nat Commun. 2024 Jan 2;15(1):155. doi: 10.1038/s41467-023-44479-2. PMID:38168102[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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