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

Authors
  • Hill, Shannon E1
  • Nguyen, Elaine1
  • Donegan, Rebecca K1
  • Patterson-Orazem, Athéna C1
  • Hazel, Anthony2
  • Gumbart, James C2
  • Lieberman, Raquel L3
  • 1 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA. , (Georgia)
  • 2 School of Physics, Georgia Institute of Technology, Atlanta, GA 30332, USA. , (Georgia)
  • 3 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA. Electronic address: [email protected] , (Georgia)
Type
Published Article
Journal
Structure
Publisher
Elsevier
Publication Date
Nov 07, 2017
Volume
25
Issue
11
Identifiers
DOI: 10.1016/j.str.2017.09.008
PMID: 29056483
Source
Medline
Keywords
License
Unknown

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.

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