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The FEBS Journal Feb 2023Disrupted protein folding or decreased protein stability can lead to the accumulation of (partially) un- or misfolded proteins, which ultimately cause the formation of... (Review)
Review
Disrupted protein folding or decreased protein stability can lead to the accumulation of (partially) un- or misfolded proteins, which ultimately cause the formation of protein aggregates. Much of the interest in protein aggregation is associated with its involvement in a wide range of human diseases and the challenges it poses for large-scale biopharmaceutical manufacturing and formulation of therapeutic proteins and peptides. On the other hand, protein aggregates can also be functional, as observed in nature, which triggered its use in the development of biomaterials or therapeutics as well as for the improvement of food characteristics. Thus, unmasking the various steps involved in protein aggregation is critical to obtain a better understanding of the underlying mechanism of amyloid formation. This knowledge will allow a more tailored development of diagnostic methods and treatments for amyloid-associated diseases, as well as applications in the fields of new (bio)materials, food technology and therapeutics. However, the complex and dynamic nature of the aggregation process makes the study of protein aggregation challenging. To provide guidance on how to analyse protein aggregation, in this review we summarize the most commonly investigated aspects of protein aggregation with some popular corresponding methods.
Topics: Humans; Protein Aggregates; Peptides; Amyloid; Protein Folding; Amyloidosis; Amyloidogenic Proteins
PubMed: 34862849
DOI: 10.1111/febs.16312 -
Nature Methods Jun 2022ColabFold offers accelerated prediction of protein structures and complexes by combining the fast homology search of MMseqs2 with AlphaFold2 or RoseTTAFold. ColabFold's...
ColabFold offers accelerated prediction of protein structures and complexes by combining the fast homology search of MMseqs2 with AlphaFold2 or RoseTTAFold. ColabFold's 40-60-fold faster search and optimized model utilization enables prediction of close to 1,000 structures per day on a server with one graphics processing unit. Coupled with Google Colaboratory, ColabFold becomes a free and accessible platform for protein folding. ColabFold is open-source software available at https://github.com/sokrypton/ColabFold and its novel environmental databases are available at https://colabfold.mmseqs.com .
Topics: Computers; Databases, Factual; Protein Folding; Proteins; Software
PubMed: 35637307
DOI: 10.1038/s41592-022-01488-1 -
Redox Biology Jul 2019Endoplasmic reticulum (ER) is a dynamic organelle orchestrating the folding and post-translational maturation of almost all membrane proteins and most secreted proteins.... (Review)
Review
Endoplasmic reticulum (ER) is a dynamic organelle orchestrating the folding and post-translational maturation of almost all membrane proteins and most secreted proteins. These proteins synthesized in the ER, need to form disulfide bridge to acquire specific three-dimensional structures for function. The formation of disulfide bridge is mediated via protein disulfide isomerase (PDI) family and other oxidoreductases, which contribute to reactive oxygen species (ROS) generation and consumption in the ER. Therefore, redox regulation of ER is delicate and sensitive to perturbation. Deregulation in ER homeostasis, usually called ER stress, can provoke unfolded protein response (UPR) pathways with an aim to initially restore homeostasis by activating genes involved in protein folding and antioxidative machinery. Over time, however, activated UPR involves a variety of cellular signaling pathways which determine the state and fate of cell in large part (like autophagy, apoptosis, ferroptosis, inflammation, senescence, stemness, and cell cycle, etc.). This review will describe the regulation of UPR from the redox perspective in controlling the cell survival or death, emphasizing the redox modifications of UPR sensors/transducers in the ER.
Topics: Animals; Autophagy; Cell Lineage; Endoplasmic Reticulum Stress; Humans; Oxidation-Reduction; Protein Folding; Unfolded Protein Response
PubMed: 30470534
DOI: 10.1016/j.redox.2018.11.005 -
Proceedings of the National Academy of... May 2023Maintaining the health of the proteome is a critical cellular task. Recently, we found G-quadruplex (G4) nucleic acids are especially potent at preventing protein...
Maintaining the health of the proteome is a critical cellular task. Recently, we found G-quadruplex (G4) nucleic acids are especially potent at preventing protein aggregation in vitro and could at least indirectly improve the protein folding environment of . However, the roles of G4s in protein folding were not yet explored. Here, through in vitro protein folding experiments, we discover that G4s can accelerate protein folding by rescuing kinetically trapped intermediates to both native and near-native folded states. Time-course folding experiments in further demonstrate that these G4s primarily improve protein folding quality in as opposed to preventing protein aggregation. The ability of a short nucleic acid to rescue protein folding opens up the possibility of nucleic acids and ATP-independent chaperones to play considerable roles in dictating the ultimate folding fate of proteins.
Topics: G-Quadruplexes; Escherichia coli; Protein Aggregates; Nucleic Acids; Protein Folding
PubMed: 37155907
DOI: 10.1073/pnas.2216308120 -
Protein Science : a Publication of the... Jul 2020The intriguing process of protein folding comprises discrete steps that stabilize the protein molecules in different conformations. The metastable state of protein is... (Review)
Review
The intriguing process of protein folding comprises discrete steps that stabilize the protein molecules in different conformations. The metastable state of protein is represented by specific conformational characteristics, which place the protein in a local free energy minimum state of the energy landscape. The native-to-metastable structural transitions are governed by transient or long-lived thermodynamic and kinetic fluctuations of the intrinsic interactions of the protein molecules. Depiction of the structural and functional properties of metastable proteins is not only required to understand the complexity of folding patterns but also to comprehend the mechanisms of anomalous aggregation of different proteins. In this article, we review the properties of metastable proteins in context of their stability and capability of undergoing atypical aggregation in physiological conditions.
Topics: Kinetics; Models, Molecular; Protein Conformation; Protein Folding; Proteins; Thermodynamics
PubMed: 32223005
DOI: 10.1002/pro.3859 -
Current Opinion in Structural Biology Aug 2021Membrane proteins account for a quarter of cellular proteins, and most are synthesised at the endoplasmic reticulum (ER). Insertion and folding of polypeptides in the... (Review)
Review
Membrane proteins account for a quarter of cellular proteins, and most are synthesised at the endoplasmic reticulum (ER). Insertion and folding of polypeptides in the membrane environment is prone to error, necessitating diverse quality control systems. Recent discoveries have demonstrated how forces act on the nascent chain during insertion, and revealed new translocon components and accessories that facilitate the correct biogenesis of substrates. Our understanding of one of the best studied quality control systems-ER-associated degradation-has been advanced through new structural and functional studies of the core Hrd1 complex, and through the discovery of a new branch of this degradative pathway. New data also reveal how cells resolve clogged translocons, which would otherwise be unable to function. Finally, new work elucidates how mitochondrial tail-anchored proteins that have been mistargeted to the ER are identified and destroyed. Overall, we describe an emerging picture of an increasingly complex quality control network.
Topics: Endoplasmic Reticulum; Membrane Proteins; Protein Folding; Quality Control
PubMed: 33857720
DOI: 10.1016/j.sbi.2021.03.003 -
Current Opinion in Structural Biology Apr 2022Proteins encounter frequent molecular interactions in biological environments. Computer simulations have become an increasingly important tool in providing mechanistic... (Review)
Review
Proteins encounter frequent molecular interactions in biological environments. Computer simulations have become an increasingly important tool in providing mechanistic insights into how such interactions in vivo relate to their biological function. The review here focuses on simulations describing protein assembly and molecular crowding effects as two important aspects that are distinguished mainly by how specific and long-lived protein contacts are. On the topic of crowding, recent simulations have provided new insights into how crowding affects protein folding and stability, modulates enzyme activity, and affects diffusive properties. Recent studies of assembly processes focus on assembly pathways, especially for virus capsids, amyloid aggregation pathways, and the role of multivalent interactions leading to phase separation. Also, discussed are technical challenges in achieving increasingly realistic simulations of interactions in cellular environments.
Topics: Amyloid; Biophysical Phenomena; Computer Simulation; Protein Folding
PubMed: 35219215
DOI: 10.1016/j.sbi.2022.102340 -
EMBO Reports Aug 2021Cell survival, tissue integrity and organismal health depend on the ability to maintain functional protein networks even under conditions that threaten protein... (Review)
Review
Cell survival, tissue integrity and organismal health depend on the ability to maintain functional protein networks even under conditions that threaten protein integrity. Protection against such stress conditions involves the adaptation of folding and degradation machineries, which help to preserve the protein network by facilitating the refolding or disposal of damaged proteins. In multicellular organisms, cells are permanently exposed to stress resulting from mechanical forces. Yet, for long time mechanical stress was not recognized as a primary stressor that perturbs protein structure and threatens proteome integrity. The identification and characterization of protein folding and degradation systems, which handle force-unfolded proteins, marks a turning point in this regard. It has become apparent that mechanical stress protection operates during cell differentiation, adhesion and migration and is essential for maintaining tissues such as skeletal muscle, heart and kidney as well as the immune system. Here, we provide an overview of recent advances in our understanding of mechanical stress protection.
Topics: Cell Survival; Protein Folding; Proteome; Proteostasis; Stress, Mechanical
PubMed: 34309183
DOI: 10.15252/embr.202152507 -
Biomolecules Jan 2020The model of protein folding proposed by Ptitsyn and colleagues involves the accretion of secondary structures around a nucleus. As developed by Efimov, this model also... (Review)
Review
The model of protein folding proposed by Ptitsyn and colleagues involves the accretion of secondary structures around a nucleus. As developed by Efimov, this model also provides a useful way to view the relationships among structures. Although somewhat eclipsed by later databases based on the pairwise comparison of structures, Efimov's approach provides a guide for the more automatic comparison of proteins based on an encoding of their topology as a string. Being restricted to layers of secondary structures based on beta sheets, this too has limitations which are partly overcome by moving to a more generalised secondary structure lattice that can encompass both open and closed (barrel) sheets as well as helical packing of the type encoded by Murzin and Finkelstein on small polyhedra. Regular (crystalline) lattices, such as close-packed hexagonals, were found to be too limited so pseudo-latticses were investigated including those found in quasicrystals and the Bernal tetrahedron-based lattice that he used to represent liquid water. The Bernal lattice was considered best and used to generate model protein structures. These were much more numerous than those seen in Nature, posing the open question of why this might be.
Topics: Algorithms; Cell Nucleus; Computer Simulation; Kinetics; Models, Molecular; Protein Folding; Protein Structure, Secondary; Proteins; Thermodynamics
PubMed: 32012781
DOI: 10.3390/biom10020193 -
Current Opinion in Structural Biology Aug 2021Membrane proteins have historically been recalcitrant to biophysical folding studies. However, recent adaptations of methods from the soluble protein folding field have... (Review)
Review
Membrane proteins have historically been recalcitrant to biophysical folding studies. However, recent adaptations of methods from the soluble protein folding field have found success in their applications to transmembrane proteins composed of both α-helical and β-barrel conformations. Avoiding aggregation is critical for the success of these experiments. Altogether these studies are leading to discoveries of folding trajectories, foundational stabilizing forces and better-defined endpoints that enable more accurate interpretation of thermodynamic data. Increased information on membrane protein folding in the cell shows that the emerging biophysical principles are largely recapitulated even in the complex biological environment.
Topics: Membrane Proteins; Protein Folding; Thermodynamics
PubMed: 33975156
DOI: 10.1016/j.sbi.2021.03.006