We are analyzing https://link.springer.com/article/10.1007/s00775-022-01946-3.

Title:
Calcium dysregulation potentiates wild-type myocilin misfolding: implications for glaucoma pathogenesis | JBIC Journal of Biological Inorganic Chemistry
Description:
Abstract Myocilin is secreted from trabecular meshwork cells to an eponymous extracellular matrix that is critical for maintaining intraocular pressure. Missense mutations found in the myocilin olfactomedin domain (OLF) lead to intracellular myocilin misfolding and are causative for the heritable form of early-onset glaucoma. The OLF domain contains a unique internal, hetero-dinuclear calcium site. Here, we tested the hypothesis that calcium dysregulation causes wild-type (WT) myocilin misfolding reminiscent of that observed for disease variants. Using two cellular models expressing WT myocilin, we show that the Ca2+ ATPase channel blocker thapsigargin inhibits WT myocilin secretion. Intracellular WT myocilin is at least partly insoluble and aggregated in the endoplasmic reticulum (ER), and stains positively with an amyloid dye. By comparing the effect of thapsigargin on WT myocilin to that on a de novo secretion-competent Ca2+-free variant D478S, we discern that non-secretion of WT myocilin is due initially to calcium dysregulation, and is potentiated further by resultant ER stress. In E. coli, depletion of calcium leads to recombinant expression of misfolded isolated WT OLF but the D478S variant is still produced as a folded monomer. Treatment of cells expressing a double mutant composed of D478S and either disease variants P370L or Y437H with thapsigargin promotes its misfolding and aggregation, demonstrating the limits of D478S to correct secretion defects. Taken together, the heterodinuclear calcium site is a liability for proper folding of myocilin. Our study suggests a molecular mechanism by which WT myocilin misfolding may contribute broadly to glaucoma-associated ER stress. Graphical abstract This study explores the effect of calcium depletion on myocilin olfactomedin domain folding.
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pubmed, article, google, scholar, cas, central, myocilin, lieberman, biol, calcium, mol, hill, chem, genet, glaucoma, content, misfolding, saccuzzo, martin, access, nguyen, res, hum, privacy, cookies, information, journal, chemistry, fingert, author, publish, search, dysregulation, emily, open, donegan, orwig, polansky, chen, clark, eye, vollrath, cell, supported, springer, site, data, log, research, wildtype,

Topics {✒️}

open-angle glaucoma month download article/chapter hetero-dinuclear calcium site related subjects article jbic journal double mutant composed bioinorganic chemistry access wild-type joe mk full article pdf donegan rk wt myocilin misfolding early-onset glaucoma intracellular myocilin misfolding myocilin misfolding reminiscent heterodinuclear calcium site van duijn cm calcium dysregulation resultant er stress intracellular wt myocilin privacy choices/manage cookies correct secretion defects myocilin olfactomedin domain cooke-bailey jn trabecular meshwork cells wiggs jl glaucoma pathogenesis igo rp jr article log european economic area eponymous extracellular matrix maintaining intraocular pressure missense mutations found stone em leary jc 3rd ethics declarations conflict article saccuzzo hill contributed equally er stress article cite conditions privacy policy amyloid dye check access faraldo-gomez jd instant access additional information publisher' calcium leads lópez-garrido mp yemo ku & raquel electronic supplementary material

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         description:Myocilin is secreted from trabecular meshwork cells to an eponymous extracellular matrix that is critical for maintaining intraocular pressure. Missense mutations found in the myocilin olfactomedin domain (OLF) lead to intracellular myocilin misfolding and are causative for the heritable form of early-onset glaucoma. The OLF domain contains a unique internal, hetero-dinuclear calcium site. Here, we tested the hypothesis that calcium dysregulation causes wild-type (WT) myocilin misfolding reminiscent of that observed for disease variants. Using two cellular models expressing WT myocilin, we show that the Ca2+ ATPase channel blocker thapsigargin inhibits WT myocilin secretion. Intracellular WT myocilin is at least partly insoluble and aggregated in the endoplasmic reticulum (ER), and stains positively with an amyloid dye. By comparing the effect of thapsigargin on WT myocilin to that on a de novo secretion-competent Ca2+-free variant D478S, we discern that non-secretion of WT myocilin is due initially to calcium dysregulation, and is potentiated further by resultant ER stress. In E. coli, depletion of calcium leads to recombinant expression of misfolded isolated WT OLF but the D478S variant is still produced as a folded monomer. Treatment of cells expressing a double mutant composed of D478S and either disease variants P370L or Y437H with thapsigargin promotes its misfolding and aggregation, demonstrating the limits of D478S to correct secretion defects. Taken together, the heterodinuclear calcium site is a liability for proper folding of myocilin. Our study suggests a molecular mechanism by which WT myocilin misfolding may contribute broadly to glaucoma-associated ER stress. This study explores the effect of calcium depletion on myocilin olfactomedin domain folding.
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      description:Myocilin is secreted from trabecular meshwork cells to an eponymous extracellular matrix that is critical for maintaining intraocular pressure. Missense mutations found in the myocilin olfactomedin domain (OLF) lead to intracellular myocilin misfolding and are causative for the heritable form of early-onset glaucoma. The OLF domain contains a unique internal, hetero-dinuclear calcium site. Here, we tested the hypothesis that calcium dysregulation causes wild-type (WT) myocilin misfolding reminiscent of that observed for disease variants. Using two cellular models expressing WT myocilin, we show that the Ca2+ ATPase channel blocker thapsigargin inhibits WT myocilin secretion. Intracellular WT myocilin is at least partly insoluble and aggregated in the endoplasmic reticulum (ER), and stains positively with an amyloid dye. By comparing the effect of thapsigargin on WT myocilin to that on a de novo secretion-competent Ca2+-free variant D478S, we discern that non-secretion of WT myocilin is due initially to calcium dysregulation, and is potentiated further by resultant ER stress. In E. coli, depletion of calcium leads to recombinant expression of misfolded isolated WT OLF but the D478S variant is still produced as a folded monomer. Treatment of cells expressing a double mutant composed of D478S and either disease variants P370L or Y437H with thapsigargin promotes its misfolding and aggregation, demonstrating the limits of D478S to correct secretion defects. Taken together, the heterodinuclear calcium site is a liability for proper folding of myocilin. Our study suggests a molecular mechanism by which WT myocilin misfolding may contribute broadly to glaucoma-associated ER stress. This study explores the effect of calcium depletion on myocilin olfactomedin domain folding.
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         Heptacoordination
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         Aggregation
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         Microbiology
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