Side-chain recognition and gating in the ribosome exit tunnel

Abstract

The ribosome is a large complex catalyst responsible for the synthesis of new proteins, an essential function for life. New proteins emerge from the ribosome through an exit tunnel as nascent polypeptide chains. Recent findings indicate that tunnel interactions with the nascent polypeptide chain might be relevant for the regulation of translation. However, the specific ribosomal structural features that mediate this process are unknown. Performing molecular dynamics simulations, we are studying the interactions between components of the ribosome exit tunnel and different chemical probes (specifically different amino acid side chains or monovalent inorganic ions). Our free-energy maps describe the physicochemical environment of the tunnel, revealing binding crevices and free-energy barriers for single amino acids and ions. Our simulations indicate that transport out of the tunnel could be different for diverse amino acid species. In addition, our results predict a notable protein-RNA interaction between a flexible 23S rRNA tetraloop (gate) and ribosomal protein L39 (latch) that could potentially obstruct the tunnel's exit. By relating our simulation data to earlier biochemical studies, we propose that ribosomal features at the exit of the tunnel can play a role in the regulation of nascent chain exit and ion flux. Moreover, our free-energy maps may provide a context for interpreting sequencedependent nascent chain phenomenology.fragment-based search ͉ free-energy calculation ͉ molecular dynamics ͉ simulation ͉ translation

A Role for the Poly(A)-binding Protein Pab1p in PUF Protein-mediated Repression

“…3D), suggesting Rpl39p may be involved in Puf5p repression either directly or indirectly. Rpl39p is part of the 60 S ribosomal subunit and participates in a gating mechanism that controls release of the polypeptide chain (41,42). In conclusion, the Pab1p-independent translational repression mechanism requires a poly(A) tail, close proximity to the ORF, and possibly Rpl39p.…”

Confined dynamics of a ribosome‐bound nascent globin: Cone angle analysis of fluorescence depolarization decays in the presence of two local motions

“…15,16 The influence of individual amino acid side chains has also been highlighted in a recent computational work. 17 Outside the ribosomal tunnel, individual nascent chain structure 18 and dynamics, 19 or lack thereof, have also been reported. Cotranslationally active chaperones bound to the ribosomal surface such as E. coli trigger factor (TF) may affect the conformational freedom of nascent proteins due to TF's proximity to the tunnel exit, 20,21 and its ability to interact with nascent chains 22,23 and protect them from proteolytic cleavage.…”

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

“…The top genes were analyzed, and knockdowns of Ribosomal protein L39 (RPL39) and Myeloid Leukemia Factor 2 (MLF2) were associated with a decrease in nitric oxide (NO) signaling (8), in particular inducible nitric oxide synthase (iNOS, NOS2). RPL39 is a structural protein of the ribosome at its polypeptide exit tunnel, a protein-sensitive channel that regulates translation through recognition of specific sequences (9,10). MLF2 is involved in chromosomal arm 12p aberrations associated with acute leukemias of lymphoid and myeloid lineage (11).…”