Structural analysis of the dynamic ribosome-translocon complex DOI Creative Commons
Aaron J. O. Lewis,

Frank Zhong,

Robert J. Keenan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 22, 2023

Abstract The protein translocon at the endoplasmic reticulum comprises Sec61 translocation channel and numerous accessory factors that collectively facilitate biogenesis of secretory membrane proteins. Here, we leveraged recent advances in cryo-EM structure prediction to derive insights into several novel configurations ribosome-translocon complex. We show how a transmembrane domain (TMD) looped configuration passes through lateral gate during insertion; nascent chain can bind constrain conformation ribosomal uL22; translocon-associated (TRAP) complex adjust its position different stages biogenesis. Most unexpectedly, find large proportion complexes contains RAMP4 intercalated Sec61’s gate, widening central pore contributing hydrophilic interior. These structures lead mechanistic hypotheses for function highlight remarkably plastic machinery whose conformations composition dynamically diverse range substrates.

Language: Английский

Toward Understanding the Mechanism of Client‐Selective Small Molecule Inhibitors of the Sec61 Translocon DOI Creative Commons

Nidhi Sorout,

Volkhard Helms

Journal of Molecular Recognition, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 12, 2024

ABSTRACT The Sec61 translocon mediates the translocation of numerous, newly synthesized precursor proteins into lumen endoplasmic reticulum or their integration its membrane. Recently, structural biology revealed conformations idle substrate‐engaged Sec61, and likewise interactions with accessory membrane Sec62, Sec63, TRAP, respectively. Several natural synthetic small molecules have been shown to block Sec61‐mediated protein translocation. Since this is a key step in biogenesis, broad inhibition generally cytotoxic, which may be problematic for putative drug target. Interestingly, several compounds exhibit client‐selective modes action, such that only certain was affected. Here, we discuss recent advances biology, molecular modelling, screening aim use as feasible

Language: Английский

Citations

0
Hibernating ribosomes tether to mitochondria as an adaptive response to cellular stress during glucose depletion DOI Open Access

Olivier Gemin,

Maciej Gluc,

Michael D. Purdy

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 8, 2023

Abstract Cell survival under nutrient-deprived conditions relies on cells’ ability to adapt their organelles and rewire metabolic pathways. In the fission yeast Schizosaccharomyces pombe , nutrient depletion is an unfavorable condition for protein synthesis triggers a response characterized by mitochondrial fragmentation sequestration of cytosolic ribosomes mitochondria. The molecular mechanism underlying ribosomal remains elusive. this study, we performed time-lapse in situ cryo-electron tomography microscopy complemented biochemical experiments elucidate details adaptive response. Our analysis indicate that upon glucose halted, causing enter inactive state conformational change obstructs peptidyl transferase center. reveal presence oligomeric arrays hibernating tethered surface. Surprisingly, bind outer membrane via small subunit, interaction facilitated RACK1-orthologue Cpc2. show ribosome tethering important cell conditions. This study broadens our understanding cellular adaptations triggered scarcity mechanisms regulate quiescence.

Language: Английский

Citations

1
Structural analysis of the dynamic ribosome-translocon complex DOI Creative Commons
Aaron J. O. Lewis,

Frank Zhong,

Robert J. Keenan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 22, 2023

Abstract The protein translocon at the endoplasmic reticulum comprises Sec61 translocation channel and numerous accessory factors that collectively facilitate biogenesis of secretory membrane proteins. Here, we leveraged recent advances in cryo-EM structure prediction to derive insights into several novel configurations ribosome-translocon complex. We show how a transmembrane domain (TMD) looped configuration passes through lateral gate during insertion; nascent chain can bind constrain conformation ribosomal uL22; translocon-associated (TRAP) complex adjust its position different stages biogenesis. Most unexpectedly, find large proportion complexes contains RAMP4 intercalated Sec61’s gate, widening central pore contributing hydrophilic interior. These structures lead mechanistic hypotheses for function highlight remarkably plastic machinery whose conformations composition dynamically diverse range substrates.

Language: Английский

Citations

0