Edward P. O'Brien, Professor of Chemistry at The Pennsylvania State University, will give a seminar titled, "How a novel class of protein misfolding is associated with changes in enzyme activity, proteostasis, aging, and disease."

This seminar will also be available by Zoom.

Zoom link https://gc-cuny.zoom.us/j/99611592897?pwd=gB1rITJuytSxEjCZIKEhpdaepER3u…
Meeting ID: 996 1159 2897.  Passcode: asrc+CCNY

Please note: 

* Full names must be used to be admitted to the Zoom meeting.

* The Zoom meeting will be closed and locked at 12:15 p.m., and no one will be able to enter the meeting after that time.

ABSTRACT

Utilizing simulations, experimental data, and data science, my lab predicted the existence of a previously undiscovered, widespread class of protein misfolding that can result in soluble, loss-of-function states, some of which evade the proteostasis network. This class of misfolding involves structural changes in geometric motifs called non-covalent lasso entanglements, which are found in 70% of the native structures of globular proteins. In this talk, I will synthesize six lines of evidence: (1) proteome-wide and atomistic simulations establish the prevalence and physical plausibility of self-entanglement misfolding; (2) translation-speed changes from synonymous mutations can re-partition folding trajectories into slowly interconverting, near-native entangled ensembles with reduced catalytic efficiency; (3) native-like surfaces coupled to these topological barriers explain how some misfolded states bypass chaperones; that these misfolded states are associated with (4) increased nascent protein degradation through the ubiquitin-proteasome pathway in human fibroblast cells, (5) with structural changes in proteins that occur during yeast mother cell aging, and (6) with a higher likelihood of harboring pathogenic mutations in human diseases. Taken together, simulations and experiments are converging on a unified picture in which entanglement misfolding is common, biologically consequential, and measurable.