Cotranslational sorting and processing of newly synthesized proteins in eukaryotes

Trends in Biochemical Sciences, Год журнала: 2023, Номер 49(2), С. 105 - 118

Опубликована: Ноя. 1, 2023

Ribosomes interact with a variety of different protein biogenesis factors that guide newly synthesized proteins to their native 3D shapes and cellular localization. Depending on the type translated substrate, distinct set cotranslational must ribosome in timely coordinated manner ensure proper biogenesis. While cytonuclear require maturation folding factors, secretory be maintained an unfolded state processed cotranslationally by transport membrane translocation factors. Here we explore specific processing steps for cytonuclear, secretory, eukaryotes then discuss how nascent polypeptide-associated complex (NAC) sorts these into correct pathway.

Язык: Английский

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Protein N-terminal modifications: molecular machineries and biological implications

Trends in Biochemical Sciences, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

The majority of eukaryotic proteins undergo N-terminal (Nt) modifications facilitated by various enzymes. These enzymes, which target the initial amino acid a polypeptide in sequence-dependent manner, encompass peptidases, transferases, cysteine oxygenases, and ligases. Nt - such as acetylation, fatty acylations, methylation, arginylation, oxidation enhance proteome complexity regulate protein targeting, stability, complex formation. Modifications at N termini are thereby core components large number biological processes, including cell signaling motility, autophagy regulation, plant animal oxygen sensing. Dysregulation Nt-modifying enzymes is implicated several human diseases. In this feature review we provide an overview occurring either co- or post-translationally, involved, impact.

Язык: Английский

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Methionine aminopeptidase 2 and its autoproteolysis product have different binding sites on the ribosome

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 24, 2024

Excision of the initiator methionine is among first co-translational processes that occur at ribosome. While this crucial step in protein maturation executed by two types aminopeptidases eukaryotes (MAP1 and MAP2), additional roles disease translational regulation have drawn more attention to MAP2. Here, we report several cryo-EM structures human fungal MAP2 80S Irrespective nascent chains, can occupy tunnel exit. On chain displaying ribosomes, MAP2-80S interaction highly dynamic MAP2-specific N-terminal extension engages stabilizing interactions with long rRNA expansion segment ES27L. Loss autoproteolytic cleavage impedes tunnel, while promoting enter ribosomal A-site, where it functional centers translation. These findings reveal proteolytic remodeling severely affects ribosome binding, set stage for targeted studies.

Язык: Английский

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Multi-protein assemblies orchestrate co-translational enzymatic processing on the human ribosome

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Сен. 3, 2024

Abstract Nascent chains undergo co-translational enzymatic processing as soon their N-terminus becomes accessible at the ribosomal polypeptide tunnel exit (PTE). In eukaryotes, N-terminal methionine excision (NME) by Methionine Aminopeptidases (MAP1 and MAP2), acetylation (NTA) N-Acetyl-Transferase A (NatA), is most common combination of subsequent modifications carried out on 80S ribosome. How these processes are coordinated in context a rapidly translating ribosome has remained elusive. Here, we report two cryo-EM structures multi-enzyme complexes assembled vacant human ribosomes, indicating routes for NME-NTA. Both assemblies form independent nascent chain substrates. Irrespective route, NatA occupies non-intrusive ‘distal’ binding site which does not interfere with MAP1 or MAP2 nor other ribosome-associated factors (RAFs). can partake coordinated, dynamic assembly through hydra-like chaperoning function abundant Polypeptide-Associated Complex (NAC). contrast to MAP1, completely covers PTE thus incompatible NAC recruitment. Together, our data provide structural framework orchestration NME NTA protein biogenesis.

Язык: Английский

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The nascent polypeptide-associated complex (NAC) as regulatory hub on ribosomes

Biological Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Abstract The correct synthesis of new proteins is essential for maintaining a functional proteome and cell viability. This process tightly regulated, with ribosomes associated protein biogenesis factors ensuring proper production, modification, targeting. In eukaryotes, the conserved nascent polypeptide-associated complex (NAC) plays central role in coordinating early processing by regulating ribosome access multiple factors. NAC recruits modifying enzymes to ribosomal exit site N-terminus directs secretory into SRP-mediated targeting pathway. this review we will focus on these pathways, which are critical summarize recent advances understanding cotranslational functions mechanisms higher eukaryotes.

Язык: Английский

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Ribosomal RNA expansion segments and their role in ribosome biology

Biochemical Society Transactions, Год журнала: 2024, Номер 52(3), С. 1317 - 1325

Опубликована: Май 2, 2024

Ribosomes are universally conserved cellular machines that catalyze protein biosynthesis. The active sites underly immense evolutionary conservation resulting in virtually identical core structures of ribosomes all domains life including organellar ribosomes. However, more peripheral cytosolic changed during evolution accommodating new functions and regulatory options. expansion occurred at the riboprotein level, larger ribosomal proteins RNA level increasing length RNA. Expansions within occur as clusters face toward periphery ribosome. Recent biochemical structural work has shed light on how rRNA-specific segments (ESs) recruit factors translation they modulate dynamics cytosol. Here we focus recent yeast, human trypanosomal explores role two specific rRNA ESs small large subunit respectively. While no single strategy exists, absence consequences for proteomic stability fitness, rendering them fascinating tools tailored

Язык: Английский

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Ribosome Structural Changes Dynamically Affect Ribosome Function

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(20), С. 11186 - 11186

Опубликована: Окт. 17, 2024

Ribosomes were known to be multicomponent complexes as early the 1960s. Nonetheless, prevailing view for decades considered active ribosomes a monolithic population, in which all are identical composition and function. This implied that themselves did not actively contribute regulation of protein synthesis. In this perspective, I review evidence different model, based on results showing can harbor types ribosomal RNA (rRNA) proteins (r-proteins) and, furthermore, need contain complete set r-proteins. also summarize recent favoring notion such distinct have affinities specific messenger RNAs may execute translation process differently. Thus, should contributors

Язык: Английский

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Diverging co-translational protein complex assembly pathways are governed by interface energy distribution

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 25, 2024

Abstract Protein-protein interactions are at the heart of all cellular processes, with ribosome emerging as a platform, orchestrating nascent-chain interplay dynamics. Here, to study characteristics governing co-translational protein folding and complex assembly, we combine selective profiling, imaging, N-terminomics all-atoms molecular Focusing on conserved N-terminal acetyltransferases (NATs), uncover diverging assembly pathways, where highly homologous subunits serve opposite functions. We find that only few residues “hotspots,” initiating upon exposure exit tunnel. These hotspots characterized by high binding energy, anchoring entire interface assembly. Alpha-helices harboring thermolabile, unfolding during simulations, depending their partner subunit avoid misfolding. In vivo hotspot mutations disrupted complexation, leading aggregation. Accordingly, conservation analysis reveals missense NATs variants, causing neurodevelopmental neurodegenerative diseases, disrupt putative clusters. Expanding our include phosphofructokinase, anthranilate synthase, nucleoporin subcomplex, employ AlphaFold-Multimer model complexes’ complete structures. Computing MD-derived energy profiles, similar trends. propose based distribution strong predictor

Язык: Английский

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Structural analysis of the dynamic ribosome-translocon complex

eLife, Год журнала: 2024, Номер 13

Опубликована: Апрель 16, 2024

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-electron microscopy (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.

Язык: Английский

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Efficient signal sequence of mRNA vaccines enhances the antigen expression to expand the immune protection against viral infection

Journal of Nanobiotechnology, Год журнала: 2024, Номер 22(1)

Опубликована: Май 28, 2024

Abstract The signal sequence played a crucial role in the efficacy of mRNA vaccines against virus pandemic by influencing antigen translation. However, limited research had been conducted to compare and analyze specific mechanisms involved. In this study, novel approach was introduced substituting enhance its immune response. Computational simulations demonstrated that various peptides differed their binding capacities with recognition particle (SRP) 54 M subunit, which positively correlated translation efficiency. Our data revealed sequences tPA IL-6-modified receptor domain (RBD) sequentially led higher expression elicited more robust humoral cellular protection SARS-CoV-2 compared original sequence. By highlighting importance sequence, provided foundational safe for ongoing modifications sequence-antigen design, aiming optimize vaccines.

Язык: Английский

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