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A research team around 2020’s Award Winner Dr. Stefan Pfeffer and cooperation partners discovered how bacteria monitor and maintain the fidelity of cellular protein synthesis.
A universally conserved molecular machine, the ribosome, is responsible for making cellular proteins. Ribosomes translate the genetic information as encoded in chain-like messenger RNA (mRNA) molecules into a sequence of consecutive amino acid residues that fold into the mature protein. However, ribosomes can get stuck in the middle of the process, inadvertently producing incomplete proteins. Because these incomplete proteins are potentially cytotoxic, cells have evolved mechanisms to recognize when ribosomes stall and to mark the incomplete proteins for degradation even before they are released into the cellular environment.
The research team identified a protein, MutS2, which senses and resolves ribosome stalling in many bacteria. By visualizing MutS2 in action using state-of-the-art cryo-electron microscopy, they could obtain a detailed mechanistic understanding of the process. MutS2 recognizes structural features that are typical to stalled ribosomes and, importantly, the ribosome must get stuck long enough for the next ribosome on the mRNA chain to collide into it. This binding mode explains how only terminally stalled ribosomes are being sensed by MutS2.
To resolve the situation, MutS2 follows two different strategies. First, MutS2 cleaves the mRNA molecule and thereby subjects it to degradation. Second, MutS2 promotes rescue of the stalled ribosome, likely by separating it into its two subunits, which is a prerequisite for the initiation of down-stream processes that eventually target the incomplete protein for degradation and thus eliminate the threat.
Failure to degrade incomplete proteins has been linked to neurodegeneration and neuromuscular diseases. Understanding this fundamental process in bacteria will thus shed light into disease mechanisms in humans, as well.
The full article can be found at:
The author Stefan Pfeffer is grateful to the Aventis Foundation for the Life Sciences Bridge Award which has importantly contributed to the success of this project.
Legend: Cryo-EM structure of the bacterial collided disome (stalled ribosome: orange; collided ribosome: green) in complex with the collision sensing protein MutS2 (blue).