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SUMMARY:Self-entangled misfolded structures are the molecular bridge conne
 cting synonymous mutations to long-timescale changes in protein structure 
 and function - Ed O'Brien\, Pennsylvania State University
DTSTART:20210331T150000Z
DTEND:20210331T160000Z
UID:TALK158110@talks.cam.ac.uk
CONTACT:Anne Jacobs
DESCRIPTION:Synonymous mutations\, which alter an mRNA sequence but not th
 e encoded protein sequence\, have been found to alter the long-timescale f
 unction of proteins\, including the specific activity of enzymes and the a
 bility of proteins to form oligomers. It is unknown how synonymous mutatio
 ns lead to such changes in protein structure and function\, and why these 
 altered structures are not fixed by the proteostasis machinery. Here\, we 
 address this gap in our knowledge using a combination of multi-scale molec
 ular modeling\, high-throughput simulations\, and meta-analysis of the lit
 erature. We first show that across the E. coli cytosolic proteome many nas
 cent proteins populate subpopulations of long-lived kinetically trapped st
 ates that are near native like but likely have reduced functionality due t
 o localized misfolding. We then show\, using coarse-grained simulations\, 
 that these near-native misfolded states can bypass E. coli chaperones beca
 use they expose similar hydrophobic surface area as the native state. We t
 hen demonstrate\, through a meta-analysis of the experimental literature\,
  that in vitro it is common for appreciable subpopulations of proteins to 
 be misfolded\, non-functional but bypass chaperones. Finally\, using multi
 -scale modeling\, we demonstrate that population shifts in kinetically tra
 pped entangled states brought about by synonymous mutations explain the re
 sulting changes in the specific activity of proteins. These studies indica
 te that there is a fourth fate of proteins in cells - near-native\, solubl
 e misfolded states that bypass the proteostasis machinery whose population
 s are influenced by changes in translation elongation speed. These results
  motivate future experimental efforts to demonstrate the existence of thes
 e entangled structures\, and the influence this 'dark proteome' has on phe
 notype
LOCATION:https://zoom.us/j/92635473991
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