The structure of a hibernating ribosome in a Lyme disease pathogen

Sharma, Manjuli R.; Manjari, Swati R.; Agrawal, Ekansh K.; Keshavan, Pooja; Koripella, Ravi K.; Majumdar, Soneya; Marcinkiewicz, Ashley L.; Lin, Yi-Pin; Agrawal, Rajendra K.; Banavali, Nilesh K.

doi:10.1038/s41467-023-42266-7

Cited by 4 publications

(4 citation statements)

References 73 publications

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“…Our inactive LSU structures resemble late intermediates of LSU biogenesis, where H68-71 are still not structured [26][27][28] . Biogenesis factors are needed to fold these 23S RNA helices in their active conformation during ribosome assembly (Figure 5h).…”

Section: Mechanisms Of Hflx-mediated Splitting and Antibiotic Resista...mentioning

confidence: 80%

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Drug resistance through ribosome splitting and rRNA disordering in mycobacteria

Majumdar,

Kashyap,

Koripella

et al. 2024

Preprint

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HflX is known to rescue stalled ribosomes and is implicated in antibiotic resistance in several bacteria. Here we present several high-resolution cryo-EM structures of mycobacterial HflX in complex with the ribosome and its 50S subunit, with and without antibiotics. These structures reveal a distinct mechanism for HflX- mediated ribosome splitting and antibiotic resistance in mycobacteria. In addition to dissociating ribosome into two subunits, mycobacterial HflX mediates persistent disordering of multiple 23S rRNA helices to generate an inactive pool of 50S subunits. Mycobacterial HflX also acts as an anti-association factor by binding to pre-dissociated 50S subunits. A mycobacteria-specific insertion in HflX reaches further into the peptidyl transferase center. The position of this insertion overlaps with ribosome-bound macrolides or lincosamide class of antibiotics. The extended conformation of insertion seen in the absence of these antibiotics retracts and adjusts around the bound antibiotics instead of physically displacing them. It therefore likely imparts antibiotic resistance by sequestration of the antibiotic- bound inactive 50S subunits.

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Section: Mechanisms Of Hflx-mediated Splitting and Antibiotic Resista...mentioning

confidence: 80%

“…S5). This suggests that these rRNA helices are disordered even after HflX dissociates from the ribosome, thus leaving behind an inactive pool of LSUs, resembling a late LSU biogenesis intermediate or an inactive LSU [26][27][28] .…”

Section: Structures Of the Mycobacterial 50s-hflx-b And 50s-hflx-c Co...mentioning

confidence: 99%

Drug resistance through ribosome splitting and rRNA disordering in mycobacteria

Majumdar,

Kashyap,

Koripella

et al. 2024

Preprint

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“…RsfS works in line with the stringent response and thus plays a key role in the translational regulation during the nutrient deprivation. The broader implications of those results are on research conducted on ribosome shutdown mechanisms which accrue in human pathogen infection processes, where the host restrains pathogen from proliferating by imposing various of stresses, such as S.aureus and B. burgdorferi (Khusainov et al, 2020; Prusa, Zhu, & Stallings, 2018; Sharma et al, 2023). Therefore, bacterial RsfS can serve as a potential drug target for antimicrobial treatments.…”

Section: Discussionmentioning

confidence: 99%

Bacteria adapt nutrient deprivation by reducing vacant 70S ribosomes via the silencing factor RsfS

Zhang,

Nikolay,

Jiang

et al. 2024

Preprint

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Bacteria downregulate protein synthesis to conserve energy during nutrient deprivation stress. The stringent response is a widely recognized strategy employed by bacteria to counter this stress by suppressing de novo ribosome synthesis, while leaving the pre-existing ribosomes unaffected. The conserved bacterial ribosome silencing factor (RsfS) has been identified as the sole factor affecting the equilibrium between pre-existing 70S ribosomes and their subunits; however, the detailed mechanism remains elusive. Here we demonstrate how bacteria adapt to nutrient deprivation through RsfS-mediated processes. During nutrient downshift, vacant 70S ribosomes (without translating mRNAs and tRNAs) tend to accumulate in the cells, causing a devastating energy drain by stimulating the activity of GTPase proteins such as EF-G. RsfS exclusively dissociates the vacant 70S ribosomes, leaving those involved in translation with tRNAs intact, thus conserving cellular energy and resources. This process facilitates the expression of enzymes essential for biosynthetic pathways and energy production. These observations reveal the translational regulatory role of RsfS in efficiently utilizing cellular resources during starvation conditions.

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“…Recent advances in cryo-electron microscopy (cryo-EM) and high-resolution X-ray analyses have provided numerous detailed structures of ribosomes from diverse sources and in different conformational states, resolved to near-atomic resolutions. These structures allow us to understand how r-proteins and rRNA regions are arranged in the most important functional centers, how ligands (mRNA, tRNAs, translational factors, and antibiotics) are positioned, and how they interact with the ribosomal components [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Extraribosomal Functions of Bacterial Ribosomal Proteins—An Update, 2023

Aseev,

Koledinskaya,

Boni

2024

IJMS

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Ribosomal proteins (r-proteins) are abundant, highly conserved, and multifaceted cellular proteins in all domains of life. Most r-proteins have RNA-binding properties and can form protein–protein contacts. Bacterial r-proteins govern the co-transcriptional rRNA folding during ribosome assembly and participate in the formation of the ribosome functional sites, such as the mRNA-binding site, tRNA-binding sites, the peptidyl transferase center, and the protein exit tunnel. In addition to their primary role in a cell as integral components of the protein synthesis machinery, many r-proteins can function beyond the ribosome (the phenomenon known as moonlighting), acting either as individual regulatory proteins or in complexes with various cellular components. The extraribosomal activities of r-proteins have been studied over the decades. In the past decade, our understanding of r-protein functions has advanced significantly due to intensive studies on ribosomes and gene expression mechanisms not only in model bacteria like Escherichia coli or Bacillus subtilis but also in little-explored bacterial species from various phyla. The aim of this review is to update information on the multiple functions of r-proteins in bacteria.

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The structure of a hibernating ribosome in a Lyme disease pathogen

Cited by 4 publications

References 73 publications

Drug resistance through ribosome splitting and rRNA disordering in mycobacteria

Drug resistance through ribosome splitting and rRNA disordering in mycobacteria

Bacteria adapt nutrient deprivation by reducing vacant 70S ribosomes via the silencing factor RsfS

Extraribosomal Functions of Bacterial Ribosomal Proteins—An Update, 2023

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