Publication: Amorphous protein aggregates related to cataracts.

Congratulations to Jennifer Boatz, Dr. Mingyue Li and our collaborators in the Gronenborn lab for the publication of our new paper on cataract-related protein aggregation. Our newly published report in Nature Communications looks at the structure of a mutant protein (P23T γD crystallin) associated with inherited cataract disease, when it is aggregated. Interestingly, the same protein forms very different kinds of deposits depending on the conditions under which it aggregates: a common type of aggregate “polymorphism”. In many studies of protein aggregation, the protein of interest is made to form aggregates by exposure to acidic conditions. This cataract protein also aggregates well under such conditions, which cause it to form worm-like amyloid fibrils. However, Jennifer also looked at the protein aggregation that happens at neutral pH, such as is present in the eye. Interestingly, this results in amorphous-looking deposits that are dramatically different from canonical amyloid. Despite looking amorphous, the aggregates give beautiful solid-state NMR spectra that reveal their internal structure to be well ordered and seemingly very similar to the native state of the protein. (Which is not the case in amyloids that form due to extensive misfolding of other proteins) The paper also talks about the potential implications for our thinking about how the cataract-related aggregation process may take place, and how such information may be useful for optimal anti-cataract drug design and screening efforts.

The full reference for the paper: Boatz, J.C., Whitley, M.J., Li, M., Gronenborn, A.M., & Van der Wel, P.C.A. (2017) Cataract-associated P23T γD-crystallin retains a native-like fold in amorphous-looking aggregates formed at physiological pH. Nat. Commun. 8:15137.

PS. Jennifer will at the upcoming FASEB SRC meeting on Protein Aggregation in Health and Disease to present this exciting work in person. We hope to see you there!