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Molecular insights into protein synthesis with proline residues.

ABSTRACT: Proline is an amino acid with a unique cyclic structure that facilitates the folding of many proteins, but also impedes the rate of peptide bond formation by the ribosome. As a ribosome substrate, proline reacts markedly slower when compared with other amino acids both as a donor and as an acceptor of the nascent peptide. Furthermore, synthesis of peptides with consecutive proline residues triggers ribosome stalling. Here, we report crystal structures of the eukaryotic ribosome bound to analogs of mono- and diprolyl-tRNAs. These structures provide a high-resolution insight into unique properties of proline as a ribosome substrate. They show that the cyclic structure of proline residue prevents proline positioning in the amino acid binding pocket and affects the nascent peptide chain position in the ribosomal peptide exit tunnel. These observations extend current knowledge of the protein synthesis mechanism. They also revise an old dogma that amino acids bind the ribosomal active site in a uniform way by showing that proline has a binding mode distinct from other amino acids.

SUBMITTER: Melnikov S

PROVIDER: S-EPMC5283605 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Molecular insights into protein synthesis with proline residues.

Melnikov Sergey S Mailliot Justine J Rigger Lukas L Neuner Sandro S Shin Byung-Sik BS Yusupova Gulnara G Dever Thomas E TE Micura Ronald R Yusupov Marat M

EMBO reports 20161108 12

Proline is an amino acid with a unique cyclic structure that facilitates the folding of many proteins, but also impedes the rate of peptide bond formation by the ribosome. As a ribosome substrate, proline reacts markedly slower when compared with other amino acids both as a donor and as an acceptor of the nascent peptide. Furthermore, synthesis of peptides with consecutive proline residues triggers ribosome stalling. Here, we report crystal structures of the eukaryotic ribosome bound to analogs ...[more]

PMID: 27827794

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Project description:Proline cis/trans isomerization governs protein local conformational changes via its local mechanical rigidity. The amyloid-disrupting capacity of proline is widely acknowledged; however, the molecular mechanism is still not clear. To understand how proline residues in polypeptide chains influence amyloid propensity, we study several truncated sequences of the TDP-43 C-terminal region (287-322) and their triple proline variants (308PPP310). We use coarse-grained molecular simulation to study the time evolution of the process of aggregation in the early stages in an effective high-concentration condition (∼25 mM). This ensures the long time scales for protein association at laboratory concentrations. We use several experimentally determined structure templates as initial structures of monomer conformations. We carry out oligomer size analysis and cluster analysis, along with several structural measures, to characterize the size distributions of oligomers and their morphological/structural properties. We show that average oligomer size is not a good indicator of amyloid propensity. Structural order and/or morphological properties are better alternatives. We show that proline variants can efficiently maintain the formation of large "ordered" oligomers of shorter truncated sequences, i.e., 307-322. This "order" maintenance is weakened when using longer truncated sequences (i.e., 287-322), leading to the formation of "disordered" oligomers. From an energy trade-off perspective, if the entropic effect is weak (short sequence length), the shape-complementarity of proline variants effectively guides the oligomerization process to form "ordered" oligomer intermediates. This leads to a distinct aggregation pathway that promotes amyloid formation (on-pathway). Strong entropic effects (long sequence length), however, would cause the formation of "disordered" oligomers. This in turn will suppress amyloid formation (off-pathway). The proline shape-complementary effects provide a guided morphological restraint to facilitate the pathways of amyloid formation. Our study supports the importance of structure-based kinetic heterogeneity of prion-like sequence fragments in driving different aggregation pathways. This work sheds light on the role of morphological and structural order of early-stage oligomeric species in regulating amyloid-disrupting capacity by prolines.

Dataset Information

Molecular insights into protein synthesis with proline residues.

Publications

Molecular insights into protein synthesis with proline residues.

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