The Glaucoma-associated Olfactomedin Domain of Myocilin Is a Novel Calcium Binding Protein

Donegan, Rebecca K.; Hill, Shannon E.; Turnage, Katherine C.; Orwig, Susan D.; Lieberman, Raquel L.

doi:10.1074/jbc.m112.408906

Cited by 25 publications

(59 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The glaucoma-causing mutation D380A has been intensively studied with regard to the loss of Ca 2ϩ -binding affinity upon mutation (52). In the gliomedin structure, we detected a bound cation (most likely sodium) that is coordinated by Asn-423, corresponding in sequence to Asp-380 in myocilin (Figs.…”

Section: Discussionmentioning

confidence: 96%

“…Notably, Asn-423 corresponds to Asp-380 in myocilin. Myocilin was shown to bind and be stabilized by calcium (52), and the D380A mutation abolished calcium binding, as well as the calcium-induced increase in protein stability. This mutation is also a disease-causing variant in myocilin (see below for more discussion on myocilin mutations).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, it is interesting to note that gliomedin is localized close to the nodes of Ranvier, at which Na ϩ will rush into the axon when a nerve impulse passes, and that it is involved in the clustering of Na v channels. Previously, Ca 2ϩ binding by myocilin was reported to increase the stability of the OLF domain (52), and the binding of metals could clearly be a common mechanism to increase OLF domain stability. The functional relevance of metal binding by OLF domains clearly requires further study.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

The Olfactomedin Domain from Gliomedin Is a β-Propeller with Unique Structural Properties

Han

Kursula

2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Olfactomedin Domain from Gliomedin Is a β-Propeller with Unique Structural Properties

Han

Kursula

2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…6 The newly found role of D380 in the calcium-binding domain of the myocilin protein adds to its importance and brings up the relevance of calcium on the olfactomedin domain stability. 56 It also points to an involvement of myocilin in the trabecular meshwork tissue calcification, which has been documented to be associated with glaucoma postmortem specimens. 4 These data would be in good agreement with 1 of the functions of the calcium binding sites, which is conferring thermal stability and proteolytic protection to extracellular proteins.…”

Section: Focused Myocilin Mutant Studiesmentioning

confidence: 96%

“…52 Recently, it has been discovered that the aspartic acid amino acid 380, which as described above, leads to the unusual event of 4 different glaucoma-causative mutants (D380N, D380A, D380G, and D380H), 55 is an integral part of a calcium-binding site buried in the olfactomedin domain. 56 The glaucoma phenotypes corresponding to the 4 residue substitutions of aspartic acid 380 present a clinical onset that is intermediate between juvenile and adult-onset glaucoma. Their IOPs are also intermediate between the severe ones of P370L and the milder one of the most common Q368X.…”

Section: Focused Myocilin Mutant Studiesmentioning

confidence: 99%

The Effects of Myocilin Expression on Functionally Relevant Trabecular Meshwork Genes: A Mini-Review

Borrás

2014

Journal of Ocular Pharmacology and Therapeutics

View full text Add to dashboard Cite

Myocilin is a secreted glaucoma-associated protein, specifically induced by dexamethasone in human trabecular meshwork cells, where it was discovered. Myocilin is expressed in several tissues of the body, but it causes disease only in the eye. The protein contains two domains: an N-terminal region with significant homologies to nonmuscle myosin, and a C-terminal region, which is similar to the olfactomedin proteins. Forty percent of myocilin undergoes an intracellular endoproteolytic cleavage by calpain II, a calcium-dependent cysteine protease, which releases the 2 domains. The protein is known to interact with intracellular and extracellular matrix proteins, and some is released into the extracellular space associated with exosomes. Myocilin mutations are linked to glaucoma and induce elevated intraocular pressure. Most of the glaucoma-causative mutations map to the olfactomedin domain, which appears to be a critical domain for the function of the protein. Myocilin mutants are misfolded, aggregate in the endoplasmic reticulum, and are not secreted. Overexpression of myocilin and of its mutants in primary human trabecular meshwork cells triggers changes in the expression of numerous genes, many of which have been known to be involved in mechanisms important for the physiology and pathology of the tissue.Here we review recent studies from our laboratory and those of others that deal with trabecular meshwork genes, which are altered by the overexpression of wild-type and glaucoma-causative mutant myocilin genes.

show abstract

Common and rare myocilin variants: Predicting glaucoma pathogenicity based on genetics, clinical, and laboratory misfolding data

et al. 2021

Self Cite

View full text Add to dashboard Cite

Rare variants of the olfactomedin domain of myocilin are considered causative for inherited, early-onset open-angle glaucoma, with a misfolding toxic gain-of-function pathogenic mechanism detailed by 20 years of laboratory research. Myocilin variants are documented in the scientific literature and identified through large-scale genetic sequencing projects such as those curated in the Genome Aggregation Database (gnomAD). In the absence of key clinical and laboratory information, however, the pathogenicity of any given variant is not clear, because glaucoma is a heterogeneous and prevalent age-onset disease, and common variants are likely benign. In this review, we reevaluate the likelihood of pathogenicity for the~100 nonsynonymous missense, insertion-deletion, and premature termination of myocilin olfactomedin variants documented in the literature. We integrate available clinical, laboratory cellular, biochemical and biophysical data, the olfactomedin domain structure, and population genetics data from gnomAD. Of the variants inspected,~50% can be binned based on a preponderance of data, leaving many of uncertain pathogenicity that motivate additional studies. Ultimately, the approach of combining metrics from different disciplines will likely resolve outstanding complexities regarding the role of this misfolding-prone protein within the context of a multifactorial and prevalent ocular disease, and pave the way for new precision medicine therapeutics.

show abstract

The Glaucoma-associated Olfactomedin Domain of Myocilin Is a Novel Calcium Binding Protein

Cited by 25 publications

References 50 publications

The Olfactomedin Domain from Gliomedin Is a β-Propeller with Unique Structural Properties

The Olfactomedin Domain from Gliomedin Is a β-Propeller with Unique Structural Properties

The Effects of Myocilin Expression on Functionally Relevant Trabecular Meshwork Genes: A Mini-Review

Common and rare myocilin variants: Predicting glaucoma pathogenicity based on genetics, clinical, and laboratory misfolding data

Contact Info

Product

Resources

About