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Title: Structure and Misfolding of the Flexible Tripartite Coiled-Coil Domain of Glaucoma-Associated Myocilin

Abstract

Glaucoma-associated myocilin is a member of the olfactomedins, a protein family involved in neuronal development and human diseases. Molecular studies of the myocilin N-terminal coiled coil demonstrate a unique tripartite architecture: a Y-shaped parallel dimer-of-dimers with distinct tetramer and dimer regions. The structure of the dimeric C-terminal 7-heptad repeats elucidates an unexpected repeat pattern involving inter-strand stabilization by oppositely charged residues. Molecular dynamics simulations reveal an alternate accessible conformation in which the terminal inter-strand disulfide limits the extent of unfolding and results in a kinked configuration. By inference, full-length myocilin is also branched, with two pairs of C-terminal olfactomedin domains. Selected variants within the N-terminal region alter the apparent quaternary structure of myocilin but do so without compromising stability or causing aggregation. In addition to increasing our structural knowledge of naturally occurring extracellular coiled coils and biomedically important olfactomedins, this work broadens the scope of protein misfolding in the pathogenesis of myocilin-associated glaucoma.

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1410116
Resource Type:
Journal Article
Resource Relation:
Journal Name: Structure; Journal Volume: 25; Journal Issue: 11
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Hill, Shannon E., Nguyen, Elaine, Donegan, Rebecca K., Patterson-Orazem, Athéna C., Hazel, Anthony, Gumbart, James C., and Lieberman, Raquel L.. Structure and Misfolding of the Flexible Tripartite Coiled-Coil Domain of Glaucoma-Associated Myocilin. United States: N. p., 2017. Web. doi:10.1016/j.str.2017.09.008.
Hill, Shannon E., Nguyen, Elaine, Donegan, Rebecca K., Patterson-Orazem, Athéna C., Hazel, Anthony, Gumbart, James C., & Lieberman, Raquel L.. Structure and Misfolding of the Flexible Tripartite Coiled-Coil Domain of Glaucoma-Associated Myocilin. United States. doi:10.1016/j.str.2017.09.008.
Hill, Shannon E., Nguyen, Elaine, Donegan, Rebecca K., Patterson-Orazem, Athéna C., Hazel, Anthony, Gumbart, James C., and Lieberman, Raquel L.. Wed . "Structure and Misfolding of the Flexible Tripartite Coiled-Coil Domain of Glaucoma-Associated Myocilin". United States. doi:10.1016/j.str.2017.09.008.
@article{osti_1410116,
title = {Structure and Misfolding of the Flexible Tripartite Coiled-Coil Domain of Glaucoma-Associated Myocilin},
author = {Hill, Shannon E. and Nguyen, Elaine and Donegan, Rebecca K. and Patterson-Orazem, Athéna C. and Hazel, Anthony and Gumbart, James C. and Lieberman, Raquel L.},
abstractNote = {Glaucoma-associated myocilin is a member of the olfactomedins, a protein family involved in neuronal development and human diseases. Molecular studies of the myocilin N-terminal coiled coil demonstrate a unique tripartite architecture: a Y-shaped parallel dimer-of-dimers with distinct tetramer and dimer regions. The structure of the dimeric C-terminal 7-heptad repeats elucidates an unexpected repeat pattern involving inter-strand stabilization by oppositely charged residues. Molecular dynamics simulations reveal an alternate accessible conformation in which the terminal inter-strand disulfide limits the extent of unfolding and results in a kinked configuration. By inference, full-length myocilin is also branched, with two pairs of C-terminal olfactomedin domains. Selected variants within the N-terminal region alter the apparent quaternary structure of myocilin but do so without compromising stability or causing aggregation. In addition to increasing our structural knowledge of naturally occurring extracellular coiled coils and biomedically important olfactomedins, this work broadens the scope of protein misfolding in the pathogenesis of myocilin-associated glaucoma.},
doi = {10.1016/j.str.2017.09.008},
journal = {Structure},
number = 11,
volume = 25,
place = {United States},
year = {Wed Nov 01 00:00:00 EDT 2017},
month = {Wed Nov 01 00:00:00 EDT 2017}
}