scholarly journals Early Scanning of Nascent Polypeptides inside the Ribosomal Tunnel by NAC

2019 ◽  
Vol 75 (5) ◽  
pp. 996-1006.e8 ◽  
Author(s):  
Martin Gamerdinger ◽  
Kan Kobayashi ◽  
Annalena Wallisch ◽  
Stefan G. Kreft ◽  
Carolin Sailer ◽  
...  
Keyword(s):  
Ribosomal Tunnel

scholarly journals Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM

2020 ◽  
Author(s):  
Anna B. Loveland ◽  
Egor Svidritskiy ◽  
Denis Susorov ◽  
Soojin Lee ◽  
Alexander Park ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Specific Binding ◽  
Structural Basis ◽  
Transferase Activity ◽  
Peptidyl Transferase ◽  
Peptidyl Transferase Center ◽  
Ribosomal Tunnel ◽  
Cellular Translation ◽  
Lateral Sclerosis ◽  
Dipeptide Repeat

AbstractToxic dipeptide repeat (DPR) proteins are produced from expanded G4C2 hexanucleotide repeats in the C9ORF72 gene, which cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥ 20 repeats inhibit the ribosome’s peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryo-EM structures reveal that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center. Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with the DPR proteins and restores peptidyl-transferase activity. Our results demonstrate that strong and specific binding of poly-PR and poly-GR in the ribosomal tunnel blocks translation, revealing the structural basis of their toxicity in C9ORF72-ALS/FTD.

Ribosomal tunnel and translation regulation

2010 ◽  
Vol 75 (13) ◽  
pp. 1501-1516 ◽  
Author(s):  
A. A. Bogdanov ◽  
N. V. Sumbatyan ◽  
A. V. Shishkina ◽  
V. V. Karpenko ◽  
G. A. Korshunova
Keyword(s):  
Translation Regulation ◽  
Ribosomal Tunnel

Born in the ribosomal tunnel

Science ◽  
2019 ◽  
Vol 365 (6456) ◽  
pp. 879.5-880
Author(s):  
Stella M. Hurtley
Keyword(s):  
Ribosomal Tunnel

scholarly journals MetAP-like Ebp1 occupies the human ribosomal tunnel exit and recruits flexible rRNA expansion segments

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Klemens Wild ◽  
Milan Aleksić ◽  
Karine Lapouge ◽  
Keven D. Juaire ◽  
Dirk Flemming ◽  
...  
Keyword(s):  
Ribosomal Tunnel

scholarly journals Early encounters of a nascent membrane protein

2005 ◽  
Vol 170 (1) ◽  
pp. 27-35 ◽  
Author(s):  
Edith N.G. Houben ◽  
Raz Zarivach ◽  
Bauke Oudega ◽  
Joen Luirink
Keyword(s):  
Membrane Protein ◽  
Ribosomal Proteins ◽  
Transmembrane Domain ◽  
Signal Recognition Particle ◽  
Chain Complex ◽  
Signal Recognition ◽  
Inner Membrane ◽  
Ribosomal Tunnel ◽  
Nascent Chain ◽  
Inner Membrane Protein

An unbiased photo–cross-linking approach was used to probe the “molecular path” of a growing nascent Escherichia coli inner membrane protein (IMP) from the peptidyl transferase center to the surface of the ribosome. The nascent chain was initially in proximity to the ribosomal proteins L4 and L22 and subsequently contacted L23, which is indicative of progression through the ribosome via the main ribosomal tunnel. The signal recognition particle (SRP) started to interact with the nascent IMP and to target the ribosome–nascent chain complex to the Sec–YidC complex in the inner membrane when maximally half of the transmembrane domain (TM) was exposed from the ribosomal exit. The combined data suggest a flexible tunnel that may accommodate partially folded nascent proteins and parts of the SRP and SecY. Intraribosomal contacts of the nascent chain were not influenced by the presence of a functional TM in the ribosome.

scholarly journals Interplay between the Ribosomal Tunnel, Nascent Chain, and Macrolides Influences Drug Inhibition

2010 ◽  
Vol 17 (5) ◽  
pp. 504-514 ◽  
Author(s):  
Agata L. Starosta ◽  
Viktoriya V. Karpenko ◽  
Anna V. Shishkina ◽  
Aleksandra Mikolajka ◽  
Natalia V. Sumbatyan ◽  
...  
Keyword(s):  
Ribosomal Tunnel ◽  
Nascent Chain ◽  
Drug Inhibition

scholarly journals Ribosome binding induces repositioning of the signal recognition particle receptor on the translocon

2015 ◽  
Vol 211 (1) ◽  
pp. 91-104 ◽  
Author(s):  
Patrick Kuhn ◽  
Albena Draycheva ◽  
Andreas Vogt ◽  
Narcis-Adrian Petriman ◽  
Lukas Sturm ◽  
...  
Keyword(s):  
Protein Targeting ◽  
Signal Recognition Particle ◽  
Resonance Energy Transfer ◽  
Chain Complex ◽  
Resonance Energy ◽  
Endoplasmic Reticulum Membrane ◽  
Signal Recognition ◽  
Ribosomal Tunnel ◽  
Nascent Chain

Cotranslational protein targeting delivers proteins to the bacterial cytoplasmic membrane or to the eukaryotic endoplasmic reticulum membrane. The signal recognition particle (SRP) binds to signal sequences emerging from the ribosomal tunnel and targets the ribosome-nascent-chain complex (RNC) to the SRP receptor, termed FtsY in bacteria. FtsY interacts with the fifth cytosolic loop of SecY in the SecYEG translocon, but the functional role of the interaction is unclear. By using photo-cross-linking and fluorescence resonance energy transfer measurements, we show that FtsY–SecY complex formation is guanosine triphosphate independent but requires a phospholipid environment. Binding of an SRP–RNC complex exposing a hydrophobic transmembrane segment induces a rearrangement of the SecY–FtsY complex, which allows the subsequent contact between SecY and ribosomal protein uL23. These results suggest that direct RNC transfer to the translocon is guided by the interaction between SRP and translocon-bound FtsY in a quaternary targeting complex.

Functional ramifications of FRET-detected nascent chain folding far inside the membrane-bound ribosome

2004 ◽  
Vol 32 (5) ◽  
pp. 668-672 ◽  
Author(s):  
A.E. Johnson
Keyword(s):  
Protein Trafficking ◽  
Protein Biosynthesis ◽  
Ribosomal Subunit ◽  
Regulatory Control ◽  
Secretory Proteins ◽  
Induced Folding ◽  
Ribosomal Tunnel ◽  
Nascent Chain ◽  
Membrane Bound ◽  
Transmembrane Sequence

During protein biosynthesis, nascent protein chains are directed along a long narrow tunnel that spans the large ribosomal subunit. It has recently become clear that this structural feature has evolved to effect regulatory control over aspects of protein synthesis and protein trafficking. Since this control is nascent chain-specific, ribosomal components that form the tunnel must be involved in recognizing selected nascent proteins as they pass by. The present study focuses on one such situation in which nascent secretory proteins and membrane proteins are distinguished by the ribosome-induced folding of the latter's hydrophobic transmembrane sequence far inside the ribosomal tunnel and close to the peptidyltransferase centre.

Chemical parameters influencing fine-tuning in the binding of macrolide antibiotics to the ribosomal tunnel

2007 ◽  
Vol 79 (6) ◽  
pp. 955-968 ◽  
Author(s):  
Erez Pyetan ◽  
David Baram ◽  
Tamar Auerbach-Nevo ◽  
Ada Yonath
Keyword(s):  
Deinococcus Radiodurans ◽  
Bacterial Species ◽  
Ribosomal Subunit ◽  
Binding Pocket ◽  
Fine Tuning ◽  
23S Rrna ◽  
Structure Based Drug Design ◽  
Altered Level ◽  
Ribosomal Tunnel ◽  
Binding Pockets

In comparison to existing structural, biochemical, and therapeutical data, the crystal structures of large ribosomal subunit from the eubacterial pathogen model Deinococcus radiodurans in complex with the 14-membered macrolides erythromycylamine, RU69874, and the 16-membered macrolide josamycin, highlighted the similarities and differences in macrolides binding to the ribosomal tunnel. The three compounds occupy the macrolide binding pocket with their desosamine or mycaminose aminosugar, the C4-C7 edge of the macrolactone ring and the cladinose sugar sharing similar positions and orientations, although the latter, known to be unnecessary for antibiotic activity, displays fewer contacts. The macrolactone ring displays altogether few contacts with the ribosome and can, therefore, tilt in order to optimize its interaction with the 23S rRNA. In addition to their contacts with nucleotides of domain V of the 23S RNA, erythromycylamine and RU69874 interact with domain II nucleotide U790, and RU69874 also reaches van der Waals distance from A752, in a fashion similar to that observed for the ketolides telithromycin and cethromycin. The variability in the sequences and consequently the diversity of the conformations of macrolide binding pockets in various bacterial species can explain the drug's altered level of effectiveness on different organisms and is thus an important factor in structure-based drug design.

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