Stable calcium-free myocilin olfactomedin domain variants reveal challenges in differentiating between benign and glaucoma-causing mutations

Hill, Shannon E.; Kwon, Michelle S.; Martin, Mackenzie D.; Suntharalingam, Amirthaa; Hazel, Anthony; Dickey, Chad A.; Gumbart, James C.; Lieberman, Raquel L.

doi:10.1074/jbc.ra119.009419

Title: Stable calcium-free myocilin olfactomedin domain variants reveal challenges in differentiating between benign and glaucoma-causing mutations

Journal Article · Tue Jul 02 00:00:00 EDT 2019 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.ra119.009419· OSTI ID:1562708

Hill, Shannon E. ^[1];

^[1]; Martin, Mackenzie D. ^[1]; Suntharalingam, Amirthaa ^[2]; Hazel, Anthony ^[1]; Dickey, Chad A. ^[2];

^[1];

^[1]

Georgia Institute of Technology, Atlanta, GA (United States)
Univ. of South Florida, Tampa, FL (United States)

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 β-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. In this study, 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-Å 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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: R01EY021205; R01EY024232; R01GM123169

OSTI ID:: 1562708

Journal Information:: Journal of Biological Chemistry, Vol. 294, Issue 34; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 9 works

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59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
protein structure
protein misfolding
protein secretion
extracellular matrix protein
x-ray crystallography
molecular dynamics
protein aggregation
glaucoma

Title: Stable calcium-free myocilin olfactomedin domain variants reveal challenges in differentiating between benign and glaucoma-causing mutations

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