PT  - JOURNAL ARTICLE
AU  - Shannon E. Hill
AU  - Elaine Nguyen
AU  - Rebecca K. Donegan
AU  - Anthony Hazel
AU  - James C. Gumbart
AU  - Raquel L. Lieberman
TI  - Structure and misfolding of the flexible tripartite coiled coil domain of glaucoma-associated myocilin
AID  - 10.1101/154112
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 154112
4099  - http://biorxiv.org/content/early/2017/06/23/154112.short
4100  - http://biorxiv.org/content/early/2017/06/23/154112.full
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.