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Modeling the Trigger Factor Molecule

NSF Award:

NSF PostDoctoral Research Fellowship in Biology  (O'Brien, Edward P)

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Chaperone molecules help proteins fold into their biologically active form; without them, proteins can misfold and aggregate, a condition that can limit healthy cellular function. Scientists have long recognized that the trigger factor (TF) molecule is one of the first chaperone molecules to interact with emerging proteins as they are synthesized inside of E. coli cells.

To learn more about this interaction, Ed O'Brien and colleagues at the University of Cambridge developed a simulation of the chaperone TF and used it to reveal three distinct molecular mechanisms by which these molecules may help nascent proteins fold and function inside of cells.

The model shows that TF can slow down nascent protein folding and it makes important new predictions about how TF works. These insights may aid in the design of more efficient biotechnology manufacturing processes involving widely used E. coli cells because TF is a major component of these cells.

The researchers used experimentally measured biophysical parameters of the molecular system, and verified the simulation behavior against an independent data set. They found TF slows down folding by three distinct kinetic trapping mechanisms: One involves a decrease in the rate of structural rearrangements due to the crowded environment created by TF; a second involves folding outside the cradle formed by TF; and the third is a completely novel mechanism involving the entanglement of the nascent chain around the TF molecule.

This simulation is particularly helpful because previous experiments lacked sufficient resolution to provide a molecular-level perspective on this process.

Image

  • chaperone trigger factor binds to a ribosome during protein synthesis
Trigger factor (gray) binds to a ribosome during protein synthesis.
Edward O'Brien, University of Cambridge

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