protein translocation
Recently Published Documents


TOTAL DOCUMENTS

1266
(FIVE YEARS 199)

H-INDEX

113
(FIVE YEARS 12)

2022 ◽  
Vol 23 (2) ◽  
pp. 584
Author(s):  
Eva Pauwels ◽  
Becky Provinciael ◽  
Anita Camps ◽  
Enno Hartmann ◽  
Kurt Vermeire

One of the reported substrates for the endoplasmic reticulum (ER) translocation inhibitor cyclotriazadisulfonamide (CADA) is DNAJC3, a chaperone of the unfolded protein response during ER stress. In this study, we investigated the impact of altered DNAJC3 protein levels on the inhibitory activity of CADA. By comparing WT DNAJC3 with a CADA-resistant DNAJC3 mutant, we observed the enhanced sensitivity of human CD4, PTK7 and ERLEC1 for CADA when DNAJC3 was expressed at high levels. Combined treatment of CADA with a proteasome inhibitor resulted in synergistic inhibition of protein translocation and in the rescue of a small preprotein fraction, which presumably corresponds to the CADA affected protein fraction that is stalled at the Sec61 translocon. We demonstrate that DNAJC3 enhances the protein translation of a reporter protein that is expressed downstream of the CADA-stalled substrate, suggesting that DNAJC3 promotes the clearance of the clogged translocon. We propose a model in which a reduced DNAJC3 level by CADA slows down the clearance of CADA-stalled substrates. This results in higher residual translocation into the ER lumen due to the longer dwelling time of the temporarily stalled substrates in the translocon. Thus, by directly reducing DNAJC3 protein levels, CADA attenuates its net down-modulating effect on its substrates.


Author(s):  
Ross Eaglesfield ◽  
Kostas Tokatlidis

Mitochondrial membrane proteins play an essential role in all major mitochondrial functions. The respiratory complexes of the inner membrane are key for the generation of energy. The carrier proteins for the influx/efflux of essential metabolites to/from the matrix. Many other inner membrane proteins play critical roles in the import and processing of nuclear encoded proteins (∼99% of all mitochondrial proteins). The outer membrane provides another lipidic barrier to nuclear-encoded protein translocation and is home to many proteins involved in the import process, maintenance of ionic balance, as well as the assembly of outer membrane components. While many aspects of the import and assembly pathways of mitochondrial membrane proteins have been elucidated, many open questions remain, especially surrounding the assembly of the respiratory complexes where certain highly hydrophobic subunits are encoded by the mitochondrial DNA and synthesised and inserted into the membrane from the matrix side. This review will examine the various assembly pathways for inner and outer mitochondrial membrane proteins while discussing the most recent structural and biochemical data examining the biogenesis process.


Author(s):  
Michael J. Ziegler ◽  
Klaus Yserentant ◽  
Valentin Dunsing ◽  
Volker Middel ◽  
Antoni J. Gralak ◽  
...  

AbstractDirect control of protein interactions by chemically induced protein proximity holds great potential for both cell and synthetic biology as well as therapeutic applications. Low toxicity, orthogonality and excellent cell permeability are important criteria for chemical inducers of proximity (CIPs), in particular for in vivo applications. Here, we present the use of the agrochemical mandipropamid (Mandi) as a highly efficient CIP in cell culture systems and living organisms. Mandi specifically induces complex formation between a sixfold mutant of the plant hormone receptor pyrabactin resistance 1 (PYR1) and abscisic acid insensitive (ABI). It is orthogonal to other plant hormone-based CIPs and rapamycin-based CIP systems. We demonstrate the applicability of the Mandi system for rapid and efficient protein translocation in mammalian cells and zebrafish embryos, protein network shuttling and manipulation of endogenous proteins.


2021 ◽  
Vol 12 ◽  
Author(s):  
Lucy Troman ◽  
Ian Collinson

Gram-negative bacteria are contained by an envelope composed of inner and outer-membranes with the peptidoglycan (PG) layer between them. Protein translocation across the inner membrane for secretion, or insertion into the inner membrane is primarily conducted using the highly conserved, hourglass-shaped channel, SecYEG: the core-complex of the Sec translocon. This transport process is facilitated by interactions with ancillary subcomplex SecDF-YajC (secretion) and YidC (insertion) forming the holo-translocon (HTL). This review recaps the transport process across the inner-membrane and then further explores how delivery and folding into the periplasm or outer-membrane is achieved. It seems very unlikely that proteins are jettisoned into the periplasm and left to their own devices. Indeed, chaperones such as SurA, Skp, DegP are known to play a part in protein folding, quality control and, if necessary degradation. YfgM and PpiD, by their association at the periplasmic surface of the Sec machinery, most probably are also involved in some way. Yet, it is not entirely clear how outer-membrane proteins are smuggled past the proteases and across the PG to the barrel-assembly machinery (BAM) and their final destination. Moreover, how can this be achieved, as is thought, without the input of energy? Recently, we proposed that the Sec and BAM translocons interact with one another, and most likely other factors, to provide a conduit to the periplasm and the outer-membrane. As it happens, numerous other specialized proteins secretion systems also form trans-envelope structures for this very purpose. The direct interaction between components across the envelope raises the prospect of energy coupling from the inner membrane for active transport to the outer-membrane. Indeed, this kind of long-range energy coupling through large inter-membrane assemblies occurs for small molecule import (e.g., nutrient import by the Ton complex) and export (e.g., drug efflux by the AcrAB-TolC complex). This review will consider this hypothetical prospect in the context of outer-membrane protein biogenesis.


2021 ◽  
Vol 22 (23) ◽  
pp. 12757
Author(s):  
Sung-jun Jung ◽  
Hyun Kim

Most secreted and membrane proteins are targeted to and translocated across the endoplasmic reticulum (ER) membrane through the Sec61 protein-conducting channel. Evolutionarily conserved Sec62 and Sec63 associate with the Sec61 channel, forming the Sec complex and mediating translocation of a subset of proteins. For the last three decades, it has been thought that ER protein targeting and translocation occur via two distinct pathways: signal recognition particle (SRP)-dependent co-translational or SRP-independent, Sec62/Sec63 dependent post-translational translocation pathway. However, recent studies have suggested that ER protein targeting and translocation through the Sec translocon are more intricate than previously thought. This review summarizes the current understanding of the molecular functions of Sec62/Sec63 in ER protein translocation.


Author(s):  
Peter Pohl

AbstractIt is my pleasure to write a few words to introduce myself to the readers of Biophysical Reviews as part of the “Meet the Councilor Series.” Currently, I am serving the second period as IUPAB councilor after having been elected first in 2017. Initially, I studied Biophysics in Moscow (Russia) and later Medicine in Halle (Germany). My scientific carrier took me from the Medical School of the Martin Luther University of Halle-Wittenberg, via the Leibniz Institute for Molecular Pharmacology (Berlin) and the Institute for Biology at the Humboldt University (Berlin) to the Physics Department of the Johannes Kepler University in Linz (Austria). My key research interests lie in the molecular mechanisms of transport phenomena occurring at the lipid membrane, including (i) spontaneous and facilitated transport of water and other small molecules across membranes in reconstituted systems, (ii) proton migration along the membrane surface, (iii) protein translocation, and (iv) bilayer mechanics. Training of undergraduate, graduate, and postdoctoral researchers from diverse academic disciplines has been—and shall remain—a consistent part of my work.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
François Enchéry ◽  
Claire Dumont ◽  
Mathieu Iampietro ◽  
Rodolphe Pelissier ◽  
Noémie Aurine ◽  
...  

AbstractNipah virus (NiV) is a highly pathogenic emerging bat-borne Henipavirus that has caused numerous outbreaks with public health concerns. It is able to inhibit the host innate immune response. Since the NF-κB pathway plays a crucial role in the innate antiviral response as a major transcriptional regulator of inflammation, we postulated its implication in the still poorly understood NiV immunopathogenesis. We report here that NiV inhibits the canonical NF-κB pathway via its nonstructural W protein. Translocation of the W protein into the nucleus causes nuclear accumulation of the cellular scaffold protein 14-3-3 in both African green monkey and human cells infected by NiV. Excess of 14-3-3 in the nucleus was associated with a reduction of NF-κB p65 subunit phosphorylation and of its nuclear accumulation. Importantly, W-S449A substitution impairs the binding of the W protein to 14-3-3 and the subsequent suppression of NF-κB signaling, thus restoring the production of proinflammatory cytokines. Our data suggest that the W protein increases the steady-state level of 14-3-3 in the nucleus and consequently enhances 14-3-3-mediated negative feedback on the NF-κB pathway. These findings provide a mechanistic model of W-mediated disruption of the host inflammatory response, which could contribute to the high severity of NiV infection.


2021 ◽  
Vol 17 (11) ◽  
pp. e1009595
Author(s):  
Tarkeshwar Kumar ◽  
Satarupa Maitra ◽  
Abdur Rahman ◽  
Souvik Bhattacharjee

Tail-anchored (TA) proteins are defined by the absence of N-terminus signal sequence and the presence of a single transmembrane domain (TMD) proximal to their C-terminus. They play fundamental roles in cellular processes including vesicular trafficking, protein translocation and quality control. Some of the TA proteins are post-translationally integrated by the Guided Entry of TA (GET) pathway to the cellular membranes; with their N-terminus oriented towards the cytosol and C-terminus facing the organellar lumen. The TA repertoire and the GET machinery have been extensively characterized in the yeast and mammalian systems, however, they remain elusive in the human malaria parasite Plasmodium falciparum. In this study, we bioinformatically predicted a total of 63 TA proteins in the P. falciparum proteome and revealed the association of a subset with the P. falciparum homolog of Get3 (PfGet3). In addition, our proximity labelling studies either definitively identified or shortlisted the other eligible GET constituents, and our in vitro association studies validated associations between PfGet3 and the corresponding homologs of Get4 and Get2 in P. falciparum. Collectively, this study reveals the presence of proteins with hallmark TA signatures and the involvement of evolutionary conserved GET trafficking pathway for their targeted delivery within the parasite.


Sign in / Sign up

Export Citation Format

Share Document