6ou2: Difference between revisions
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The entry | ==Crystal Structure of the D478N Variant of the Myocilin Olfactomedin Domain== | ||
<StructureSection load='6ou2' size='340' side='right'caption='[[6ou2]], [[Resolution|resolution]] 1.96Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6ou2]] 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=6OU2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OU2 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]] 1.963Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=6ou2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ou2 OCA], [https://pdbe.org/6ou2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ou2 RCSB], [https://www.ebi.ac.uk/pdbsum/6ou2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ou2 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/MYOC_HUMAN MYOC_HUMAN] Congenital glaucoma;Juvenile glaucoma. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. MYOC mutations may contribute to GLC3A via digenic inheritance with CYP1B1 and/or another locus associated with the disease (PubMed:15733270).<ref>PMID:15733270</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/MYOC_HUMAN MYOC_HUMAN] Secreted glycoprotein regulating the activation of different signaling pathways in adjacent cells to control different processes including cell adhesion, cell-matrix adhesion, cytoskeleton organization and cell migration. Promotes substrate adhesion, spreading and formation of focal contacts. Negatively regulates cell-matrix adhesion and stress fiber assembly through Rho protein signal transduction. Modulates the organization of actin cytoskeleton by stimulating the formation of stress fibers through interactions with components of Wnt signaling pathways. Promotes cell migration through activation of PTK2 and the downstream phosphatidylinositol 3-kinase signaling. Plays a role in bone formation and promotes osteoblast differentiation in a dose-dependent manner through mitogen-activated protein kinase signaling. Mediates myelination in the peripheral nervous system through ERBB2/ERBB3 signaling. Plays a role as a regulator of muscle hypertrophy through the components of dystrophin-associated protein complex. Involved in positive regulation of mitochondrial depolarization. Plays a role in neurite outgrowth. May participate in the obstruction of fluid outflow in the trabecular meshwork.<ref>PMID:17516541</ref> <ref>PMID:17984096</ref> <ref>PMID:18855004</ref> <ref>PMID:19188438</ref> <ref>PMID:19959812</ref> <ref>PMID:21656515</ref> <ref>PMID:23629661</ref> <ref>PMID:23897819</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Nonsynonymous gene mutations can be beneficial, neutral, or detrimental to the stability, structure, and biological function of the encoded protein, but the effects of these mutations are often not readily predictable. For example, the beta-propeller olfactomedin domain of myocilin (mOLF) exhibits a complex interrelationship among structure(s), stability, and aggregation. Numerous mutations within mOLF are linked to glaucoma; the resulting variants are less stable, aggregation-prone, and sequestered intracellularly, causing cytotoxicity. Here, we report the first stable mOLF variants carrying substitutions in the calcium-binding site that exhibit solution characteristics indistinguishable from those of glaucoma variants. Crystal structures of these stable variants at 1.8-2.0-A resolution revealed features that we could not predict by molecular dynamics simulations, including loss of loop structure, helix unwinding, and a blade shift. Double mutants that combined a stabilizing substitution and a selected glaucoma-causing single-point mutant rescued in vitro folding and stability defects. In the context of full-length myocilin, secretion of stable single variants was indistinguishable from that of the WT protein, and the double mutants were secreted to varying extents. In summary, our finding that mOLF can tolerate particular substitutions that render the protein stable despite a conformational switch emphasizes the complexities in differentiating between benign and glaucoma-causing variants and provides new insight into the possible biological function of myocilin. | |||
Stable calcium-free myocilin olfactomedin domain variants reveal challenges in differentiating between benign and glaucoma-causing mutations.,Hill SE, Kwon MS, Martin MD, Suntharalingam A, Hazel A, Dickey CA, Gumbart JC, Lieberman RL J Biol Chem. 2019 Aug 23;294(34):12717-12728. doi: 10.1074/jbc.RA119.009419. Epub , 2019 Jul 2. PMID:31270212<ref>PMID:31270212</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6ou2" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Hill SE]] | |||
[[Category: Kwon MS]] | |||
[[Category: Lieberman RL]] | |||
Latest revision as of 15:58, 6 November 2024
Crystal Structure of the D478N Variant of the Myocilin Olfactomedin DomainCrystal Structure of the D478N Variant of the Myocilin Olfactomedin Domain
Structural highlights
DiseaseMYOC_HUMAN Congenital glaucoma;Juvenile glaucoma. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. MYOC mutations may contribute to GLC3A via digenic inheritance with CYP1B1 and/or another locus associated with the disease (PubMed:15733270).[1] FunctionMYOC_HUMAN Secreted glycoprotein regulating the activation of different signaling pathways in adjacent cells to control different processes including cell adhesion, cell-matrix adhesion, cytoskeleton organization and cell migration. Promotes substrate adhesion, spreading and formation of focal contacts. Negatively regulates cell-matrix adhesion and stress fiber assembly through Rho protein signal transduction. Modulates the organization of actin cytoskeleton by stimulating the formation of stress fibers through interactions with components of Wnt signaling pathways. Promotes cell migration through activation of PTK2 and the downstream phosphatidylinositol 3-kinase signaling. Plays a role in bone formation and promotes osteoblast differentiation in a dose-dependent manner through mitogen-activated protein kinase signaling. Mediates myelination in the peripheral nervous system through ERBB2/ERBB3 signaling. Plays a role as a regulator of muscle hypertrophy through the components of dystrophin-associated protein complex. Involved in positive regulation of mitochondrial depolarization. Plays a role in neurite outgrowth. May participate in the obstruction of fluid outflow in the trabecular meshwork.[2] [3] [4] [5] [6] [7] [8] [9] Publication Abstract from PubMedNonsynonymous gene mutations can be beneficial, neutral, or detrimental to the stability, structure, and biological function of the encoded protein, but the effects of these mutations are often not readily predictable. For example, the beta-propeller olfactomedin domain of myocilin (mOLF) exhibits a complex interrelationship among structure(s), stability, and aggregation. Numerous mutations within mOLF are linked to glaucoma; the resulting variants are less stable, aggregation-prone, and sequestered intracellularly, causing cytotoxicity. Here, we report the first stable mOLF variants carrying substitutions in the calcium-binding site that exhibit solution characteristics indistinguishable from those of glaucoma variants. Crystal structures of these stable variants at 1.8-2.0-A resolution revealed features that we could not predict by molecular dynamics simulations, including loss of loop structure, helix unwinding, and a blade shift. Double mutants that combined a stabilizing substitution and a selected glaucoma-causing single-point mutant rescued in vitro folding and stability defects. In the context of full-length myocilin, secretion of stable single variants was indistinguishable from that of the WT protein, and the double mutants were secreted to varying extents. In summary, our finding that mOLF can tolerate particular substitutions that render the protein stable despite a conformational switch emphasizes the complexities in differentiating between benign and glaucoma-causing variants and provides new insight into the possible biological function of myocilin. Stable calcium-free myocilin olfactomedin domain variants reveal challenges in differentiating between benign and glaucoma-causing mutations.,Hill SE, Kwon MS, Martin MD, Suntharalingam A, Hazel A, Dickey CA, Gumbart JC, Lieberman RL J Biol Chem. 2019 Aug 23;294(34):12717-12728. doi: 10.1074/jbc.RA119.009419. Epub , 2019 Jul 2. PMID:31270212[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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