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Cold Spring Harbor Perspectives in... Jan 2020Cells invest in an extensive network of factors to maintain protein homeostasis (proteostasis) and prevent the accumulation of potentially toxic protein aggregates. This... (Review)
Review
Cells invest in an extensive network of factors to maintain protein homeostasis (proteostasis) and prevent the accumulation of potentially toxic protein aggregates. This proteostasis network (PN) comprises the machineries for the biogenesis, folding, conformational maintenance, and degradation of proteins with molecular chaperones as central coordinators. Here, we review recent progress in understanding the modular architecture of the PN in mammalian cells and how it is modified during cell differentiation. We discuss the capacity and limitations of the PN in maintaining proteome integrity in the face of proteotoxic stresses, such as aggregate formation in neurodegenerative diseases. Finally, we outline various pharmacological interventions to ameliorate proteostasis imbalance.
Topics: Animals; Cell Differentiation; Homeostasis; Humans; Molecular Chaperones; Neurodegenerative Diseases; Protein Conformation; Protein Denaturation; Protein Folding; Proteins; Proteome; Proteostasis; Thermodynamics
PubMed: 30833457
DOI: 10.1101/cshperspect.a033951 -
ACS Chemical Biology Jun 2018Since the proposal of Anfinsen's thermodynamic hypothesis in 1963, our understanding of protein folding and dynamics has gained significant appreciation of its nuance... (Review)
Review
Since the proposal of Anfinsen's thermodynamic hypothesis in 1963, our understanding of protein folding and dynamics has gained significant appreciation of its nuance and complexity. Intrinsically disordered proteins, chameleonic sequences, morpheeins, and metamorphic proteins have broadened the protein folding paradigm. Here, we discuss noncanonical protein folding patterns, with an emphasis on metamorphic proteins, and we review known metamorphic proteins that occur naturally and that have been engineered in the laboratory. Finally, we discuss research areas surrounding metamorphic proteins that are primed for future exploration, including evolution, drug discovery, and the quest for previously unrecognized metamorphs. As we enter an age where we are capable of complex bioinformatic searches and de novo protein design, we are primed to search for previously unrecognized metamorphic proteins and to design our own metamorphs to act as targeted, switchable drugs; biosensors; and more.
Topics: Animals; Bacteria; Humans; Intrinsically Disordered Proteins; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Engineering; Protein Folding; Protein Unfolding
PubMed: 29787234
DOI: 10.1021/acschembio.8b00276 -
Current Opinion in Structural Biology Feb 2022Delineating the folding steps of helical-bundle membrane proteins has been a challenging task. Many questions remain unanswered, including the conformation and stability... (Review)
Review
Delineating the folding steps of helical-bundle membrane proteins has been a challenging task. Many questions remain unanswered, including the conformation and stability of the states populated during folding, the shape of the energy barriers between the states, and the role of lipids as a solvent in mediating the folding. Recently, theoretical frames have matured to a point that permits detailed dissection of the folding steps, and advances in experimental techniques at both single-molecule and ensemble levels enable selective modulation of specific steps for quantitative determination of the folding energy landscapes. We also discuss how lipid molecules would play an active role in shaping the folding energy landscape of membrane proteins, and how folding of multi-domain membrane proteins can be understood based on our current knowledge. We conclude this review by offering an outlook for emerging questions in the study of membrane protein folding.
Topics: Membrane Proteins; Protein Folding; Thermodynamics
PubMed: 34995926
DOI: 10.1016/j.sbi.2021.11.013 -
Annual Review of Biophysics May 2023My accidental encounter with protein hydrogen exchange (HX) at its very beginning and its continued development through my scientific career have led us to a series of... (Review)
Review
My accidental encounter with protein hydrogen exchange (HX) at its very beginning and its continued development through my scientific career have led us to a series of advances in HX measurement, interpretation, and cutting edge biophysical applications. After some thoughts about how life brought me there, I take the opportunity to reflect on our early studies of allosteric structure and energy change in hemoglobin, the still-current protein folding problem, and our most recent forward-looking studies on protein machines.
Topics: Biophysics; Protein Folding
PubMed: 36630583
DOI: 10.1146/annurev-biophys-062122-093517 -
Journal of Proteome Research Feb 2023The structure of a protein defines its function and integrity and correlates with the protein folding stability (PFS). Quantifying PFS allows researchers to assess...
The structure of a protein defines its function and integrity and correlates with the protein folding stability (PFS). Quantifying PFS allows researchers to assess differential stability of proteins in different disease or ligand binding states, providing insight into protein efficacy and potentially serving as a metric of protein quality. There are a number of mass spectrometry (MS)-based methods to assess PFS, such as hermal rotein rofiling (TPP), tability of roteins from ates of idation (SPROX), and odination rotein tability ssay (IPSA). Despite the critical value that PFS studies add to the understanding of mechanisms of disease and treatment development, proteomics research is still primarily dominated by concentration-based studies. We found that a major reason for the lack of PFS studies is the lack of a user-friendly data processing tool. Here we present the first user-friendly software, C with a graphical user interface for calculating PFS. Besides calculating site-specific PFS of a given protein from chemical denature folding stability assays, C is also compatible with thermal denature folding stability assays. C also includes a set of data visualization tools to help identify changes in PFS across protein sequences and in between different treatment conditions. We expect the introduction of C to lower the barrier of entry for researchers to investigate PFS, promoting the usage of PFS in studies. In the long run, we expect this increase in PFS research to accelerate our understanding of the pathogenesis and pathophysiology of disease.
Topics: Proteins; Mass Spectrometry; Protein Stability; Amino Acid Sequence; Software; Protein Folding
PubMed: 36707058
DOI: 10.1021/acs.jproteome.2c00619 -
Journal of the Royal Society, Interface Oct 2018Although it is now relatively well understood how sequence defines and impacts global protein stability in specific structural contexts, the question of how sequence... (Review)
Review
Although it is now relatively well understood how sequence defines and impacts global protein stability in specific structural contexts, the question of how sequence modulates the configurational landscape of proteins remains to be defined. Protein configurational equilibria are generally characterized by using various chemical denaturants or by changing temperature or pH. Another thermodynamic parameter which is less often used in such studies is high hydrostatic pressure. This review discusses the basis for pressure effects on protein structure and stability, and describes how the unique mechanisms of pressure-induced unfolding can provide unique insights into protein conformational landscapes.
Topics: Animals; Pressure; Protein Denaturation; Protein Stability; Proteins; Thermodynamics
PubMed: 30282759
DOI: 10.1098/rsif.2018.0244 -
Essays in Biochemistry Dec 2022How do proteins interact in the cellular environment? Which interactions stabilize liquid-liquid phase separated condensates? Are the concepts, which have been developed...
How do proteins interact in the cellular environment? Which interactions stabilize liquid-liquid phase separated condensates? Are the concepts, which have been developed for specific protein complexes also applicable to higher-order assemblies? Recent discoveries prompt for a universal framework for protein interactions, which can be applied across the scales of protein communities. Here, we discuss how our views on protein interactions have evolved from rigid structures to conformational ensembles of proteins and discuss the open problems, in particular related to biomolecular condensates. Protein interactions have evolved to follow changes in the cellular environment, which manifests in multiple modes of interactions between the same partners. Such cellular context-dependence requires multiplicity of binding modes (MBM) by sampling multiple minima of the interaction energy landscape. We demonstrate that the energy landscape framework of protein folding can be applied to explain this phenomenon, opening a perspective toward a physics-based, universal model for cellular protein behaviors.
Topics: Proteins; Protein Folding
PubMed: 36416856
DOI: 10.1042/EBC20220044 -
Current Opinion in Structural Biology Jun 2023This review outlines the effect of disease-causing mutations on proteins' thermodynamics. Two major thermodynamics quantities, which are essential for structural... (Review)
Review
This review outlines the effect of disease-causing mutations on proteins' thermodynamics. Two major thermodynamics quantities, which are essential for structural integrity, the folding and binding free energy changes caused by missense mutations, are considered. It is emphasized that disease effects in case of complex diseases may originate from several mutations over several genes, while monogenic diseases are caused by mutation is a single gene. Nevertheless, in both cases it is shown that pathogenic mutations cause larger perturbations of the above-mentioned thermodynamics quantities as compared with the benign mutations. Recent works demonstrating the effect of pathogenic mutations on the above-mentioned thermodynamics quantities, as well as on structural dynamics and allosteric pathways, are reviewed.
Topics: Virulence; Protein Folding; Mutation; Proteins; Thermodynamics
PubMed: 36965249
DOI: 10.1016/j.sbi.2023.102572 -
FEBS Letters Sep 2017
Topics: Imaging, Three-Dimensional; Middle East; Protein Folding; Signal Transduction; Societies, Medical
PubMed: 28876461
DOI: 10.1002/1873-3468.12789 -
Journal of Biomolecular NMR Apr 2022NMR-spectroscopy has certain unique advantages for recording unfolding transitions of proteins compared e.g. to optical methods. It enables per-residue monitoring and...
NMR-spectroscopy has certain unique advantages for recording unfolding transitions of proteins compared e.g. to optical methods. It enables per-residue monitoring and separate detection of the folded and unfolded state as well as possible equilibrium intermediates. This allows a detailed view on the state and cooperativity of folding of the protein of interest and the correct interpretation of subsequent experiments. Here we summarize in detail practical and theoretical aspects of such experiments. Certain pitfalls can be avoided, and meaningful simplification can be made during the analysis. Especially a good understanding of the NMR exchange regime and relaxation properties of the system of interest is beneficial. We show by a global analysis of signals of the folded and unfolded state of GB1 how accurate values of unfolding can be extracted and what limits different NMR detection and unfolding methods. E.g. commonly used exchangeable amides can lead to a systematic under determination of the thermodynamic protein stability. We give several perspectives of how to deal with more complex proteins and how the knowledge about protein stability at residue resolution helps to understand protein properties under crowding conditions, during phase separation and under high pressure.
Topics: Magnetic Resonance Spectroscopy; Nuclear Magnetic Resonance, Biomolecular; Protein Denaturation; Protein Folding; Protein Unfolding; Proteins; Thermodynamics
PubMed: 34984658
DOI: 10.1007/s10858-021-00389-3