Robert Newberry’s latest work investigating how α-synuclein responds to perturbations of cellular proteostasis is published in ACS chemical biology
DGL post-doc Robert Newberry and graduate student Alison Maxwell published paper in ACS chemical biology this week investigating how a toxic conformation of α-synuclein, a dynamic protein linked to Parkinson’s disease, responds to perturbations of cellular proteostasis using deep mutational scanning.
Robert with Martin Kampmann led this study with the graduate students in the UCSF Integrative Program in Quantitative Biology to provide authentic research experience in the classroom. A great passion and an awesome job, Robert!
In the study, the authors screened a comprehensive library of α-synuclein missense mutants in yeast cells treated with a variety of small molecules that perturb cellular processes linked to α-synuclein biology and pathobiology. Authors found that the conformation of α-synuclein previously shown to drive yeast toxicity—an extended, membrane-bound helix—is largely unaffected by these chemical perturbations, underscoring the importance of this conformational state as a driver of cellular toxicity.
On the other hand, the chemical perturbations have a significant effect on the ability of mutations to suppress α-synuclein toxicity. Moreover, the sequence determinants of α-synuclein toxicity are well described by a simple structural model of the membrane-bound helix.
This model predicts that α-synuclein penetrates the membrane to constant depth across its length but that membrane affinity decreases toward the C-terminus, which is consistent with orthogonal biophysical measurements.