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International Journal of Molecular... Feb 2020Rab GTPases play key roles in various cellular processes. They are essential, among other roles, to membrane trafficking and intracellular signaling events. Both... (Review)
Review
Rab GTPases play key roles in various cellular processes. They are essential, among other roles, to membrane trafficking and intracellular signaling events. Both trafficking and signaling events are crucial for proper embryonic development. Indeed, embryogenesis is a complex process in which cells respond to various signals and undergo dramatic changes in their shape, position, and function. Over the last few decades, cellular studies have highlighted the novel signaling roles played by Rab GTPases, while numerous studies have shed light on the important requirements of Rab proteins at various steps of embryonic development. In this review, we aimed to generate an overview of Rab contributions during animal embryogenesis. We first briefly summarize the involvement of Rabs in signaling events. We then extensively highlight the contribution of Rabs in shaping metazoan development and conclude with new approaches that will allow investigation of Rab functions in vivo.
Topics: Animals; Embryonic Development; Humans; Protein Transport; Signal Transduction; rab GTP-Binding Proteins
PubMed: 32033485
DOI: 10.3390/ijms21031064 -
Biological Chemistry May 2020Mitochondrial precursor proteins with amino-terminal presequences are imported via the presequence pathway, utilizing the TIM23 complex for inner membrane translocation.... (Review)
Review
Mitochondrial precursor proteins with amino-terminal presequences are imported via the presequence pathway, utilizing the TIM23 complex for inner membrane translocation. Initially, the precursors pass the outer membrane through the TOM complex and are handed over to the TIM23 complex where they are sorted into the inner membrane or translocated into the matrix. This handover process depends on the receptor proteins at the inner membrane, Tim50 and Tim23, which are critical for efficient import. In this review, we summarize key findings that shaped the current concepts of protein translocation along the presequence import pathway, with a particular focus on the precursor handover process from TOM to the TIM23 complex. In addition, we discuss functions of the human TIM23 pathway and the recently uncovered pathogenic mutations in TIM50.
Topics: Carrier Proteins; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Protein Transport
PubMed: 32074073
DOI: 10.1515/hsz-2020-0101 -
International Journal of Molecular... Dec 2021Looking at the variety of the thousands of different polypeptides that have been focused on in the research on the endoplasmic reticulum from the last five decades... (Review)
Review
Looking at the variety of the thousands of different polypeptides that have been focused on in the research on the endoplasmic reticulum from the last five decades taught us one humble lesson: no one size fits all. Cells use an impressive array of components to enable the safe transport of protein cargo from the cytosolic ribosomes to the endoplasmic reticulum. Safety during the transit is warranted by the interplay of cytosolic chaperones, membrane receptors, and protein translocases that together form functional networks and serve as protein targeting and translocation routes. While two targeting routes to the endoplasmic reticulum, SRP (signal recognition particle) and GET (guided entry of tail-anchored proteins), prefer targeting determinants at the N- and C-terminus of the cargo polypeptide, respectively, the recently discovered SND (SRP-independent) route seems to preferentially cater for cargos with non-generic targeting signals that are less hydrophobic or more distant from the termini. With an emphasis on targeting routes and protein translocases, we will discuss those functional networks that drive efficient protein topogenesis and shed light on their redundant and dynamic nature in health and disease.
Topics: Animals; Cytosol; Endoplasmic Reticulum; Humans; Protein Sorting Signals; Protein Transport; Proteins; Signal Recognition Particle
PubMed: 35008565
DOI: 10.3390/ijms23010143 -
Nature Reviews. Endocrinology Jan 2023The global prevalences of obesity and type 2 diabetes mellitus have reached epidemic status, presenting a heavy burden on society. It is therefore essential to find... (Review)
Review
The global prevalences of obesity and type 2 diabetes mellitus have reached epidemic status, presenting a heavy burden on society. It is therefore essential to find novel mechanisms and targets that could be utilized in potential treatment strategies and, as such, intracellular membrane trafficking has re-emerged as a regulatory tool for controlling metabolic homeostasis. Membrane trafficking is an essential physiological process that is responsible for the sorting and distribution of signalling receptors, membrane transporters and hormones or other ligands between different intracellular compartments and the plasma membrane. Dysregulation of intracellular transport is associated with many human diseases, including cancer, neurodegeneration, immune deficiencies and metabolic diseases, such as type 2 diabetes mellitus and its associated complications. This Review focuses on the latest advances on the role of endosomal membrane trafficking in metabolic physiology and pathology in vivo, highlighting the importance of this research field in targeting metabolic diseases.
Topics: Humans; Diabetes Mellitus, Type 2; Endosomes; Protein Transport; Cell Membrane; Homeostasis
PubMed: 36216881
DOI: 10.1038/s41574-022-00737-9 -
The Protein Journal Aug 2019The twin-arginine protein translocation (Tat) system has been characterized in bacteria, archaea and the chloroplast thylakoidal membrane. This system is distinct from... (Review)
Review
The twin-arginine protein translocation (Tat) system has been characterized in bacteria, archaea and the chloroplast thylakoidal membrane. This system is distinct from other protein transport systems with respect to two key features. Firstly, it accepts cargo proteins with an N-terminal signal peptide that carries the canonical twin-arginine motif, which is essential for transport. Second, the Tat system only accepts and translocates fully folded cargo proteins across the respective membrane. Here, we review the core essential features of folded protein transport via the bacterial Tat system, using the three-component TatABC system of Escherichia coli and the two-component TatAC systems of Bacillus subtilis as the main examples. In particular, we address features of twin-arginine signal peptides, the essential Tat components and how they assemble into different complexes, mechanistic features and energetics of Tat-dependent protein translocation, cytoplasmic chaperoning of Tat cargo proteins, and the remarkable proofreading capabilities of the Tat system. In doing so, we present the current state of our understanding of Tat-dependent protein translocation across biological membranes, which may serve as a lead for future investigations.
Topics: Arginine; Bacillus subtilis; Cell Membrane; Escherichia coli; Escherichia coli Proteins; Membrane Transport Proteins; Protein Folding; Protein Sorting Signals; Protein Transport; SEC Translocation Channels; Twin-Arginine-Translocation System
PubMed: 31401776
DOI: 10.1007/s10930-019-09859-y -
International Journal of Molecular... Nov 2021Most secreted and membrane proteins are targeted to and translocated across the endoplasmic reticulum (ER) membrane through the Sec61 protein-conducting channel.... (Review)
Review
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.
Topics: Endoplasmic Reticulum; Heat-Shock Proteins; Membrane Transport Proteins; Protein Processing, Post-Translational; Protein Transport; SEC Translocation Channels; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 34884562
DOI: 10.3390/ijms222312757 -
Current Opinion in Structural Biology Aug 2021
Topics: Protein Folding; Protein Transport; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 34312035
DOI: 10.1016/j.sbi.2021.06.014 -
Experimental Dermatology Nov 2023PKM2 mediates the Warburg effects and is crucial for tumorigenesis, but its role in hyperplastic skin disorders remains elusive. In this study, we investigated the...
PKM2 mediates the Warburg effects and is crucial for tumorigenesis, but its role in hyperplastic skin disorders remains elusive. In this study, we investigated the function of PKM2 in psoriatic keratinocytes. We found that PKM2 expression and its nuclear translocation were induced in the epidermis of psoriasis patients, contributing to aerobic glycolysis and cell growth. Moreover, mass spectrometry combined with immunoprecipitation analysis revealed that PKM2 could interact with TRIM33, an E3 ubiquitin ligase in the nucleus, and this interaction is critical for the nuclear retention of PKM2. As a result of TRIM33-mediated ubiquitination, PKM2 nuclear protein kinase function is promoted, thus leading to the phosphorylation of STAT3. In addition, blocking PKM2 nuclear translocation abrogated TRIM33-triggered glycolysis and cell proliferation in keratinocytes. Taken together, our experiments demonstrate that ubiquitination regulates the nuclear retention of PKM2 in keratinocytes. Moreover, our results highlight a novel mechanism accounting for the metabolic reprogramming of keratinocytes in psoriasis patients.
Topics: Humans; Cell Line, Tumor; Glycolysis; Keratinocytes; Phosphorylation; Protein Transport; Psoriasis; Transcription Factors; Thyroid Hormone-Binding Proteins
PubMed: 37688280
DOI: 10.1111/exd.14922 -
Methods in Molecular Biology (Clifton,... 2021The study of lipid-protein interactions is crucial for understanding reactions of proteins involved in lipid metabolism, lipid transport, and lipid signaling. Different...
The study of lipid-protein interactions is crucial for understanding reactions of proteins involved in lipid metabolism, lipid transport, and lipid signaling. Different detection methods can be employed for the identification of lipid-binding interactions. Isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) spectroscopy enable real-time monitoring of lipid protein interactions and provide thermodynamic parameters of the interacting partners. However, these technologies depend on the availability of the large equipment, limiting the practicability in many laboratories. Protein-lipid overlay assays are a simple first approach to screen for protein interactions with different lipids or lipid intermediates and are independent of large equipment. Subsequently, specific interactions can be analyzed in detail using protein-liposome association assays.
Topics: Calorimetry; Kinetics; Lipid Metabolism; Lipids; Liposomes; Protein Binding; Protein Interaction Mapping; Protein Transport; Proteins; Surface Plasmon Resonance; Thermodynamics
PubMed: 34047989
DOI: 10.1007/978-1-0716-1362-7_22 -
Toxins Jul 2019Pertussis toxin (PT) is a multimeric complex of six proteins. The PTS1 subunit is an ADP-ribosyltransferase that inactivates the alpha subunit of heterotrimeric G/... (Review)
Review
Pertussis toxin (PT) is a multimeric complex of six proteins. The PTS1 subunit is an ADP-ribosyltransferase that inactivates the alpha subunit of heterotrimeric G/ proteins. The remaining PT subunits form a pentamer that positions PTS1 in and above the central cavity of the triangular structure. Adhesion of this pentamer to glycoprotein or glycolipid conjugates on the surface of a target cell leads to endocytosis of the PT holotoxin. Vesicle carriers then deliver the holotoxin to the endoplasmic reticulum (ER) where PTS1 dissociates from the rest of the toxin, unfolds, and exploits the ER-associated degradation pathway for export to the cytosol. Refolding of the cytosolic toxin allows it to regain an active conformation for the disruption of cAMP-dependent signaling events. This review will consider the intracellular trafficking of PT and the order-disorder-order transitions of PTS1 that are essential for its cellular activity.
Topics: Animals; Cytosol; Humans; Pertussis Toxin; Protein Subunits; Protein Transport
PubMed: 31349590
DOI: 10.3390/toxins11080437