ArticleJournal of molecular biology2014
The glaucoma-associated olfactomedin domain of myocilin forms polymorphic fibrils that are constrained by partial unfolding and peptide sequence.
Article in Journal of molecular biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 42 citations in OpenAlex.
- Detection of non-native species formed during fibrillization of the myocilin olfactomedin domain.Protein science : a publication of the Protein Society · 2025Article
- Structural basis for anomalous cellular trafficking behavior of glaucoma-associated A427T mutant myocilin.bioRxiv : the preprint server for biology · 2025Article
- Article
- Protein misfolding and mitochondrial dysfunction in glaucoma.Frontiers in cell and developmental biology · 2025Review
- Evidence for SbioRxiv : the preprint server for biology · 2024Article
- Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming β-propeller.Nature communications · 2024Article
- Therapeutic potential of archaeal unfoldase PANet and the gateless T20S proteasome in P23H rhodopsin retinitis pigmentosa mice.PloS one · 2024Article
- Myocilin misfolding and glaucoma: A 20-year update.Progress in retinal and eye research · 2023Review
- Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability.Disease models & mechanisms · 2023Article
- Amyloid fibrillation of the glaucoma associated myocilin protein is inhibited by epicatechin gallate (ECG).RSC advances · 2022Article
- Calcium dysregulation potentiates wild-type myocilin misfolding: implications for glaucoma pathogenesis.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2022Article
- Structure‒function‒pathogenicity analysis of C-terminal myocilin missense variants based on experiments and 3D models.Frontiers in genetics · 2022Article
- Molecular architecture and modifications of full-length myocilin.Experimental eye research · 2021Article
- Common and rare myocilin variants: Predicting glaucoma pathogenicity based on genetics, clinical, and laboratory misfolding data.Human mutation · 2021Review
- Molecular Insights into Myocilin and Its Glaucoma-Causing Misfolded Olfactomedin Domain Variants.Accounts of chemical research · 2021Review
- Structural Arrangement within a Peptide Fibril Derived from the Glaucoma-Associated Myocilin Olfactomedin Domain.The journal of physical chemistry. B · 2021Article
- Myocilin-associated Glaucoma: A Historical Perspective and Recent Research Progress.Molecular vision · 2021Review
- Different Grp94 components interact transiently with the myocilin olfactomedin domain in vitro to enhance or retard its amyloid aggregation.Scientific reports · 2019Article
- Calcium-ligand variants of the myocilin olfactomedin propeller selected from invertebrate phyla reveal cross-talk with N-terminal blade and surface helices.Acta crystallographica. Section D, Structural biology · 2019Article
- Stable calcium-free myocilin olfactomedin domain variants reveal challenges in differentiating between benign and glaucoma-causing mutations.The Journal of biological chemistry · 2019Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The glaucoma-associated olfactomedin domain of myocilin (myoc-OLF) is a recent addition to the growing list of disease-associated amyloidogenic proteins. Inherited, disease-causing myocilin variants aggregate intracellularly instead of being secreted to the trabecular meshwork, which is a scenario toxic to trabecular meshwork cells and leads to early onset of ocular hypertension, the major risk factor for glaucoma. Here we systematically structurally and biophysically dissected myoc-OLF to better understand its amyloidogenesis. Under mildly destabilizing conditions, wild-type myoc-OLF adopts non-native structures that readily fibrillize when incubated at a temperature just below the transition for tertiary unfolding. With buffers at physiological pH, two main endpoint fibril morphologies are observed: (a) straight fibrils common to many amyloids and (b) unique micron-length, ~300 nm or larger diameter, species that lasso oligomers, which also exhibit classical spectroscopic amyloid signatures. Three disease-causing variants investigated herein exhibit non-native tertiary structures under physiological conditions, leading to a variety of growth rates and a fibril morphologies. In particular, the well-documented D380A variant, which lacks calcium, forms large circular fibrils. Two amyloid-forming peptide stretches have been identified, one for each of the main fibril morphologies observed. Our study places myoc-OLF within the larger landscape of the amylome and provides insight into the diversity of myoc-OLF aggregation that plays a role in glaucoma pathogenesis.
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