How a novel class of protein misfolding is associated with changes in enzyme activity, proteostasis, aging, and disease
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; (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 areconverging on a unified picture in which entanglement misfolding is common, biologically consequential, and measurable.
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Please contact Hyacinth Camillieri at hcamillieri@gc.cuny.edu if you have any questions.