RT Journal Article
SR Electronic
T1 Structure and misfolding of the flexible tripartite coiled coil domain of glaucoma-associated myocilin
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 154112
DO 10.1101/154112
A1 Shannon E. Hill
A1 Elaine Nguyen
A1 Rebecca K. Donegan
A1 Anthony Hazel
A1 James C. Gumbart
A1 Raquel L. Lieberman
YR 2017
UL http://biorxiv.org/content/early/2017/06/23/154112.abstract
AB Glaucoma-associated myocilin is a member of the olfactomedins, a protein family broadly involved in neuronal development and human disease. Molecular studies of the myocilin N-terminal coiled coil demonstrate a unique tripartite architecture: a disulfide-linked, parallel dimer-of-dimers Y-shaped molecule, with distinct tetramer and dimer regions. The structure of the C-terminal 7-heptad dimer elucidates an unexpected repeat pattern involving electrostatic inter-strand stabilization. Molecular dynamics simulations reveal an alternate conformation in which the terminal inter-strand disulfide bond limits the extent of unfolding and results in a kinked configuration. Taken together, 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 extracellular coiled coils for protein design and biomedically important olfactomedins, this work broadens the scope of protein misfolding in the pathogenesis of myocilin-associated glaucoma.Glaucoma-causing extracellular protein associated with amyloid forming propensityStructural studies confirm tripartite parallel dimer-of-dimers coiled coilLeucine zipper exhibits non-canonical heptad repeat pattern with disulfide capGlaucoma-associated variants in tetramer alter structure but not stabilityeTOC blurb Hill et al describe the structure of the coiled-coil region of myocilin, the extracellular olfactomedin family member closely associated with the ocular disorder glaucoma. Myocilin’s coiled coil adopts a unique Y-shaped parallel dimer-of-timers employing an unusual heptad repeat pattern. Selected disease variants alter quaternary structure.