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Traffic (Copenhagen, Denmark) Oct 2015Protein translocation into the endoplasmic reticulum (ER) constitutes the first step of protein secretion. ER protein import is essential in all eukaryotic cells and is... (Review)
Review
Protein translocation into the endoplasmic reticulum (ER) constitutes the first step of protein secretion. ER protein import is essential in all eukaryotic cells and is particularly critical in fast-growing tumour cells. Thus, the process can serve as target both for potential cancer drugs and for bacterial virulence factors. Inhibitors of protein transport across the ER membrane range from broad-spectrum to highly substrate-specific and can interfere with virtually any stage of this multistep process, and even with transport of endocytosed antigens into the cytosol for cross-presentation.
Topics: Animals; Antineoplastic Agents; Cytosol; Endoplasmic Reticulum; Humans; Membrane Transport Proteins; Protein Transport
PubMed: 26122014
DOI: 10.1111/tra.12308 -
The Protein Journal Aug 2019The translocation of proteins across membranes is a fundamental cellular function. Bacteria have evolved a striking array of pathways for delivering proteins into or... (Review)
Review
The translocation of proteins across membranes is a fundamental cellular function. Bacteria have evolved a striking array of pathways for delivering proteins into or across cytoplasmic membranes and, when present, outer membranes. Translocated proteins can form part of the membrane landscape, reside in the periplasmic space situated between the inner and outer membranes of Gram-negative bacteria, deposit on the cell surface, or be released to the extracellular milieu or injected directly into target cells. One protein translocation system, the general secretory pathway, is conserved in all domains of life. A second, the twin-arginine translocation pathway, is also phylogenetically distributed among most bacteria and plant chloroplasts. While all cell types have evolved additional systems dedicated to the translocation of protein cargoes, the number of such systems in bacteria is now known to exceed nine. These dedicated protein translocation systems, which include the types 1 through 9 secretion systems (T1SSs-T9SSs), the chaperone-usher pathway, and type IV pilus system, are the subject of this review. Most of these systems were originally identified and have been extensively characterized in Gram-negative or diderm (two-membrane) species. It is now known that several of these systems also have been adapted to function in Gram-positive or monoderm (single-membrane) species, and at least one pathway is found only in monoderms. This review briefly summarizes the distinctive mechanistic and structural features of each dedicated pathway, as well as the shared properties, that together account for the broad biological diversity of protein translocation in bacteria.
Topics: Bacteria; Bacterial Proteins; Bacterial Secretion Systems; Cell Membrane; Molecular Chaperones; Protein Transport
PubMed: 31407127
DOI: 10.1007/s10930-019-09862-3 -
Biochimica Et Biophysica Acta Mar 2011Protein translocation into the endoplasmic reticulum (ER) is the first and decisive step in the biogenesis of most extracellular and many soluble organelle proteins in... (Review)
Review
Protein translocation into the endoplasmic reticulum (ER) is the first and decisive step in the biogenesis of most extracellular and many soluble organelle proteins in eukaryotic cells. It is mechanistically related to protein export from eubacteria and archaea and to the integration of newly synthesized membrane proteins into the ER membrane and the plasma membranes of eubacteria and archaea (with the exception of tail anchored membrane proteins). Typically, protein translocation into the ER involves cleavable amino terminal signal peptides in precursor proteins and sophisticated transport machinery components in the cytosol, the ER membrane, and the ER lumen. Depending on the hydrophobicity and/or overall amino acid content of the precursor protein, transport can occur co- or posttranslationally. The respective mechanism determines the requirements for certain cytosolic transport components. The two mechanisms merge at the level of the ER membrane, specifically, at the heterotrimeric Sec61 complex present in the membrane. The Sec61 complex provides a signal peptide recognition site and forms a polypeptide conducting channel. Apparently, the Sec61 complex is gated by various ligands, such as signal peptides of the transport substrates, ribosomes (in cotranslational transport), and the ER lumenal molecular chaperone, BiP. Binding of BiP to the incoming polypeptide contributes to efficiency and unidirectionality of transport. Recent insights into the structure of the Sec61 complex and the comparison of the transport mechanisms and machineries in the yeast Saccharomyces cerevisiae, the human parasite Trypanosoma brucei, and mammals have various important mechanistic as well as potential medical implications. This article is part of a Special Issue entitled Protein translocation across or insertion into membranes.
Topics: Animals; Endoplasmic Reticulum; Humans; Intracellular Membranes; Protein Transport
PubMed: 20599535
DOI: 10.1016/j.bbamem.2010.06.015 -
Biochimica Et Biophysica Acta Nov 2013Co-translational protein targeting to the endoplasmic reticulum (ER), represents an evolutionary-conserved mechanism to target proteins into the secretory pathway. In... (Review)
Review
Co-translational protein targeting to the endoplasmic reticulum (ER), represents an evolutionary-conserved mechanism to target proteins into the secretory pathway. In this targeting pathway proteins possessing signal sequences are recognised at the ribosome by the signal recognition particle while they are still undergoing synthesis. This triggers their delivery to the ER protein translocation channel, where they are directly translocated into the ER. Here we review the current understanding of this translocation pathway and how molecular details obtained in the related bacterial system have provided insight into the mechanism of targeting and translocation. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.
Topics: Animals; Endoplasmic Reticulum; Humans; Protein Biosynthesis; Protein Transport; Proteins; Signal Recognition Particle
PubMed: 23481039
DOI: 10.1016/j.bbamcr.2013.02.021 -
Biological Chemistry May 2017In peroxisomal matrix protein import two processes directly depend on the binding and hydrolysis of ATP, both taking place at the late steps of the peroxisomal import... (Review)
Review
In peroxisomal matrix protein import two processes directly depend on the binding and hydrolysis of ATP, both taking place at the late steps of the peroxisomal import cycle. First, ATP hydrolysis is required to initiate a ubiquitin-transfer cascade to modify the import (co-)receptors. These receptors display a dual localization in the cytosol and at the peroxisomal membrane, whereas only the membrane bound fraction receives the ubiquitin modification. The second ATP-dependent process of the import cycle is carried out by the two AAA+-proteins Pex1p and Pex6p. These ATPases form a heterohexameric complex, which is recruited to the peroxisomal import machinery by the membrane anchor protein Pex15p. The Pex1p/Pex6p complex recognizes the ubiquitinated import receptors, pulls them out of the membrane and releases them into the cytosol. There the deubiquitinated receptors are provided for further rounds of import. ATP binding and hydrolysis are required for Pex1p/Pex6p complex formation and receptor export. In this review, we summarize the current knowledge on the peroxisomal import cascade. In particular, we will focus on the ATP-dependent processes, which are so far best understood in the model organism Saccharomyces cerevisiae.
Topics: Adenosine Triphosphate; Animals; Humans; Peroxisomes; Protein Transport; Saccharomyces cerevisiae Proteins; Ubiquitination
PubMed: 27977397
DOI: 10.1515/hsz-2016-0293 -
Critical Reviews in Biochemistry and... Apr 2019The endoplasmic reticulum (ER) is a complex, multifunctional organelle comprised of a continuous membrane and lumen that is organized into a number of functional... (Review)
Review
The endoplasmic reticulum (ER) is a complex, multifunctional organelle comprised of a continuous membrane and lumen that is organized into a number of functional regions. It plays various roles including protein translocation, folding, quality control, secretion, calcium signaling, and lipid biogenesis. Cellular protein homeostasis is maintained by a complicated chaperone network, and the largest functional family within this network consists of proteins containing tetratricopeptide repeats (TPRs). TPRs are well-studied structural motifs that mediate intermolecular protein-protein interactions, supporting interactions with a wide range of ligands or substrates. Seven TPR-containing proteins have thus far been shown to localize to the ER and control protein organization and homeostasis within this multifunctional organelle. Here, we discuss the roles of these proteins in controlling ER processes and organization. The crucial roles that TPR-containing proteins play in the ER are highlighted by diseases or defects associated with their mutation or disruption.
Topics: Animals; Calcium; Endoplasmic Reticulum; Humans; Models, Molecular; Molecular Chaperones; Protein Interaction Maps; Protein Transport; Proteins; Proteostasis; Tetratricopeptide Repeat
PubMed: 31023093
DOI: 10.1080/10409238.2019.1590305 -
PLoS Computational Biology Mar 2021In this study, we used a computational approach to investigate the early evolutionary history of a system of proteins that, together, embed and translocate other...
In this study, we used a computational approach to investigate the early evolutionary history of a system of proteins that, together, embed and translocate other proteins across cell membranes. Cell membranes comprise the basis for cellularity, which is an ancient, fundamental organizing principle shared by all organisms and a key innovation in the evolution of life on Earth. Two related requirements for cellularity are that organisms are able to both embed proteins into membranes and translocate proteins across membranes. One system that accomplishes these tasks is the signal recognition particle (SRP) system, in which the core protein components are the paralogs, FtsY and Ffh. Complementary to the SRP system is the Sec translocation channel, in which the primary channel-forming protein is SecY. We performed phylogenetic analyses that strongly supported prior inferences that FtsY, Ffh, and SecY were all present by the time of the last universal common ancestor of life, the LUCA, and that the ancestor of FtsY and Ffh existed before the LUCA. Further, we combined ancestral sequence reconstruction and protein structure and function prediction to show that the LUCA had an SRP system and Sec translocation channel that were similar to those of extant organisms. We also show that the ancestor of Ffh and FtsY that predated the LUCA was more similar to FtsY than Ffh but could still have comprised a rudimentary protein translocation system on its own. Duplication of the ancestor of FtsY and Ffh facilitated the specialization of FtsY as a membrane bound receptor and Ffh as a cytoplasmic protein that could bind nascent proteins with specific membrane-targeting signal sequences. Finally, we analyzed amino acid frequencies in our ancestral sequence reconstructions to infer that the ancestral Ffh/FtsY protein likely arose prior to or just after the completion of the canonical genetic code. Taken together, our results offer a window into the very early evolutionary history of cellularity.
Topics: Bacterial Proteins; Cell Membrane; Escherichia coli; Escherichia coli Proteins; Evolution, Molecular; Models, Biological; Phylogeny; Protein Transport; Receptors, Cytoplasmic and Nuclear; SEC Translocation Channels; Signal Recognition Particle
PubMed: 33684113
DOI: 10.1371/journal.pcbi.1008623 -
Proceedings of the National Academy of... Jan 2023Secretory proteins are cotranslationally or posttranslationally translocated across lipid membranes via a protein-conducting channel named SecY in prokaryotes and Sec61...
Secretory proteins are cotranslationally or posttranslationally translocated across lipid membranes via a protein-conducting channel named SecY in prokaryotes and Sec61 in eukaryotes. The vast majority of secretory proteins in bacteria are driven through the channel posttranslationally by SecA, a highly conserved ATPase. How a polypeptide chain is moved by SecA through the SecY channel is poorly understood. Here, we report electron cryomicroscopy structures of the active SecA-SecY translocon with a polypeptide substrate. The substrate is captured in different translocation states when clamped by SecA with different nucleotides. Upon binding of an ATP analog, SecA undergoes global conformational changes to push the polypeptide substrate toward the channel in a way similar to how the RecA-like helicases translocate their nucleic acid substrates. The movements of the polypeptide substrates in the SecA-SecY translocon share a similar structural basis to those in the ribosome-SecY complex during cotranslational translocation.
Topics: SecA Proteins; Bacterial Proteins; SEC Translocation Channels; Models, Molecular; Protein Transport; Peptides; Escherichia coli Proteins
PubMed: 36598944
DOI: 10.1073/pnas.2208070120 -
Cellular and Molecular Life Sciences :... Jan 2010In the three domains of life, the Sec, YidC/Oxa1, and Tat translocases play important roles in protein translocation across membranes and membrane protein insertion.... (Review)
Review
In the three domains of life, the Sec, YidC/Oxa1, and Tat translocases play important roles in protein translocation across membranes and membrane protein insertion. While extensive studies have been performed on the endoplasmic reticular and Escherichia coli systems, far fewer studies have been done on archaea, other Gram-negative bacteria, and Gram-positive bacteria. Interestingly, work carried out to date has shown that there are differences in the protein transport systems in terms of the number of translocase components and, in some cases, the translocation mechanisms and energy sources that drive translocation. In this review, we will describe the different systems employed to translocate and insert proteins across or into the cytoplasmic membrane of archaea and bacteria.
Topics: Adenosine Triphosphatases; Archaea; Archaeal Proteins; Bacteria; Bacterial Proteins; Cell Membrane; Membrane Transport Proteins; Protein Transport; SEC Translocation Channels; SecA Proteins
PubMed: 19823765
DOI: 10.1007/s00018-009-0160-x -
Molecular Therapy : the Journal of the... May 2021Circular RNAs (circRNAs) are RNAs with a unique circular structure that is generated from back-splicing processes. These circular molecules were discovered more than 40... (Review)
Review
Circular RNAs (circRNAs) are RNAs with a unique circular structure that is generated from back-splicing processes. These circular molecules were discovered more than 40 years ago but failed to raise scientific interest until lately. Increasing studies have found that these circular RNAs might not just be byproducts of the splicing process but possess important regulatory functions through different cellular events. Most circular RNAs are currently being studied in the field of cancer, and many of them have been confirmed to be involved in the process of tumorigenesis. However, many circular RNAs are implicated in the developmental stages of diseases other than cancer. In this review, we focus on discussing the role of circular RNAs in non-cancer diseases, especially in cardiovascular diseases. Following the summary of the life cycle of circRNAs, we provide input on studying circRNA-protein interactions based on our experience, which modulate protein translocation. Furthermore, we outline the potential of circRNAs to be potent biomarkers, effective therapeutic targets, and potential treatments in cardiovascular diseases as well as other non-cancer fields.
Topics: Cardiovascular Diseases; Early Diagnosis; Genetic Markers; Humans; Molecular Targeted Therapy; Protein Transport; Proteins; RNA, Circular
PubMed: 33484969
DOI: 10.1016/j.ymthe.2021.01.018