TCB Publications - Abstract

James Gumbart, Eduard Schreiner, Daniel N. Wilson, Roland Beckmann, and Klaus Schulten. Mechanisms of SecM-mediated stalling in the ribosome. Biophysical Journal, 103:331-341, 2012. (PMC: 3400775)

GUMB2012 Nascent-peptide modulation of translation is a common regulatory mechanism of gene expression. In this mechanism, while still in the exit tunnel of the ribosome, the nascent peptide induces translational pausing, thereby controlling the expression of downstream genes. One example is SecM, which inhibits peptide-bond formation in the ribosome’s peptidyl transferase center (PTC) during its own translation, up-regulating the expression of the protein translocase SecA. While biochemical experiments and cryo-electron microscopy data have led to the identification of some residues involved in SecM recognition, the full pathway of interacting residues connecting SecM to the PTC through the ribosome has not yet been conclusively established. Now, using the cryo-electron microscopy data an atomic model of the SecM-stalled ribosome is derived via molecular dynamics flexible fitting, complete with P- and A-site tRNAs. Subsequently, simulations of native and mutated SecM-stalled ribosomes have been carried out to investigate possible interaction pathways between a critical SecM residue, R163, and the PTC. The simulations reveal, in particular, the role of SecM in altering the position of the tRNAs in the ribosome, thus demonstrating how the presence of SecM in the exit tunnel induces stalling. Finally, steered molecular dynamics simulations pulling SecM towards the tunnel exit suggest how SecA interacting with SecM from outside the ribosome relieves stalling.

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