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This review is an update of an article published four years ago (Uversky V.N. (2009) Intrinsically disordered proteins in neurodegenerative diseases: another illustration of the D~2 concept. Frontiers in Bioscience 14, 5188-5238)....
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This review is an update of an article published four years ago (Uversky V.N. (2009) Intrinsically disordered proteins in neurodegenerative diseases: another illustration of the D~2 concept. Frontiers in Bioscience 14, 5188-5238). The major goal of this review is to show the interconnections between intrinsically disordered proteins (IDPs) and human neurodegeneration. This brings to existence a new D3 concept: protein intrinsic Disorder in neuroDegenerative Diseases. An important aspect of the D3 concept is that it deals with three D~3's, emphasizing that intrinsically Disordered proteins are abundantly found in various neuroDegenerative Diseases (the first D~3), that these IDPs provoke neuroDegeneration due to their Dysfunctionality (the second D~3), and that neuroDegeneration-related IDPs are often controlled by other Disordered proteins (the third D~3).
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A universal method that improves protein stability and evolution has thus far eluded discovery. Recently, however, studies have shown that insertional fusion to a protein chaperone stabilized various target proteins with minimal n...
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A universal method that improves protein stability and evolution has thus far eluded discovery. Recently, however, studies have shown that insertional fusion to a protein chaperone stabilized various target proteins with minimal negative effects. The improved stability was derived from insertion into a hyperthermophilic protein, Pyrococcus furiosus maltodextrin-binding protein (PfMBP), rather than from changes to the target protein sequence. In this report, by evaluating the thermodynamic and kinetic stability of various inserted -lactamase (BLA) homologues, we were able to examine the molecular determinants of stability realized by insertional fusion to PfMBP. Results indicated that enhanced stability and suppressed aggregation of BLA stemmed from enthalpic and entropic mechanisms. This report also suggests that insertional fusion to a stable protein scaffold has the potential to be a useful method for improving protein stability, as well as functional protein evolution.
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Intrinsic disorder (i.e., lack of a unique 3-D structure) is a common phenomenon, and many biologically active proteins are disordered as a whole, or contain long disordered regions. These intrinsically disordered proteins/regions...
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Intrinsic disorder (i.e., lack of a unique 3-D structure) is a common phenomenon, and many biologically active proteins are disordered as a whole, or contain long disordered regions. These intrinsically disordered proteins/regions constitute a significant part of all proteomes, and their functional repertoire is complementary to functions of ordered proteins. In fact, intrinsic disorder represents an important driving force for many specific functions. An illustrative example of such disordercentric functional class is RNA-binding proteins. In this study, we present the results of comprehensive bioinformatics analyses of the abundance and roles of intrinsic disorder in 3,411 ribosomal proteins from 32 species. We show that many ribosomal proteins are intrinsically disordered or hybrid proteins that contain ordered and disordered domains. Predicted globular domains of many ribosomal proteins contain noticeable regions of intrinsic disorder. We also show that disorder in ribosomal proteins has different characteristics compared to other proteins that interact with RNA and DNA including overall abundance, evolutionary conservation, and involvement in protein–protein interactions. Furthermore, intrinsic disorder is not only abundant in the ribosomal proteins, but we demonstrate that it is absolutely necessary for their various functions.
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The formation of inclusion bodies (IBs)-amorphous aggregates of misfolded insoluble protein-during recombinant protein expression, is still one of the biggest bottlenecks in protein science. We have developed and analyzed a rapid ...
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The formation of inclusion bodies (IBs)-amorphous aggregates of misfolded insoluble protein-during recombinant protein expression, is still one of the biggest bottlenecks in protein science. We have developed and analyzed a rapid parallel approach for matrix-assisted refolding of recombinant His,tagged proteins. Efficiencies of matrix-assisted refolding were screened in a 96-well format. The developed methodology allowed the efficient refolding of five different test proteins, including monomeric and oligomeric proteins. Compared to refolding in-solution, the matrix-assisted refolding strategy proved equal or better for all five proteins tested. Interestingly, specifically oligomeric proteins displayed significantly higher levels of refolding compared to refolding in-solution. Mechanistically, matrix-assisted folding seems to differ from folding in-solution, as the reaction proceeds more rapidly and shows a remarkably different concentration dependence-it allows refolding at up to 1000-fold higher protein concentration than folding in-solution.
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Abstract Scoring docking solutions is a difficult task, and many methods have been developed for this purpose. In docking, only a handful of the hundreds of thousands of models generated by docking algorithms are acceptable, causi...
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Abstract Scoring docking solutions is a difficult task, and many methods have been developed for this purpose. In docking, only a handful of the hundreds of thousands of models generated by docking algorithms are acceptable, causing difficulties when developing scoring functions. Today's best scoring functions can significantly increase the number of top‐ranked models but still fail for most targets. Here, we examine the possibility of utilizing predicted interface residues to score docking models generated during the scan stage of a docking algorithm. Many methods have been developed to infer the regions of a protein surface that interact with another protein, but most have not been benchmarked using docking algorithms. This study systematically tests different interface prediction methods for scoring >300.000 low‐resolution rigid‐body template free docking decoys. Overall we find that contact‐based interface prediction by BIPSPI is the best method to score docking solutions, with >12% of first ranked docking models being acceptable. Additional experiments indicated precision as a high‐importance metric when estimating interface prediction quality, focusing on docking constraints production. Finally, we discussed several limitations for adopting interface predictions as constraints in a docking protocol.
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Protein–protein interactions form central elements of almost all cellular processes. Knowledge of the structure of protein–protein complexes but also of the binding affinity is of major importance to un
Protein–protein interactions form central elements of almost all cellular processes. Knowledge of the structure of protein–protein complexes but also of the binding affinity is of major importance to understand the biological function of protein–protein interactions. Even weak transient protein–protein interactions can be of functional relevance for the cell during signal transduction or regulation of metabolism. The structure of a growing number of protein–protein complexes has been solved in recent years. Combined with docking approaches or template‐based methods, it is possible to generate structural models of many putative protein–protein complexes or to design new protein–protein interactions. In order to evaluate the functional relevance of putative or predicted protein–protein complexes, realistic binding affinity prediction is of increasing importance. Several computational tools ranging from simple force‐field or knowledge‐based scoring of single protein–protein complexes to ensemble‐based approaches and rigorous binding free energy simulations are available to predict relative and absolute binding affinities of complexes. With a focus on molecular mechanics force‐field approaches the present review aims at presenting an overview on available methods and discussing advantages, approximations, and limitations of the various methods.
This article is categorized under:
Molecular and Statistical Mechanics > Molecular InteractionsMolecular and Statistical Mechanics > Free Energy MethodsSoftware > Molecular Modeling
摘要 :
Intrinsically disordered proteins (IDPs) exist and function without well-defined three-dimensional structures, thus they defy the classical structure-function paradigm. These proteins are common in proteomes, and they carry out es...
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Intrinsically disordered proteins (IDPs) exist and function without well-defined three-dimensional structures, thus they defy the classical structure-function paradigm. These proteins are common in proteomes, and they carry out essential functions often related to signalling and regulation of transcription. Herein, the experimental evidence for their lack of structure and the major functional benefits that structural disorder confers, are surveyed. It is shown that IDPs often function by molecular recognition, in which either short motifs, or domain-sized disordered segments are used for partner recognition. In both cases, the binding segment undergoes induced folding and it attains an ordered structure. This folding-upon-binding scenario suggests that the function of IDPs can be interpreted in terms of the static structural view of the classical paradigm. New developments in the field, however, suggest that folding upon binding is limited, and many IDPs preserve a significant level of disorder in the bound state, a phenomenon termed fuzziness. In addition, IDPs may structurally adapt to different partners with different functional outcomes, resulting in promiscuity in function termed moonlighting. It is suggested that a new model describing the structure-function relationship of Ups has to encompass such structural and functional promiscuity inherent in the disordered state of IDPs.
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Calmodulin (CaM) is a universal regulator for a huge number of proteins in all eukaryotic cells. Best known is its function as a calcium-dependent modulator of the activity of enzymes, such as protein kinases and phosphatases, as ...
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Calmodulin (CaM) is a universal regulator for a huge number of proteins in all eukaryotic cells. Best known is its function as a calcium-dependent modulator of the activity of enzymes, such as protein kinases and phosphatases, as well as other signaling proteins including membrane receptors, channels and structural proteins. However, less well known is the fact that CaM can also function as a CO-dependent adaptor protein, either by bridging between different domains of the same protein or by linking two identical or different target proteins together. These activities are possible due to the fact that CaM contains two independently-folded Ca2+ binding lobes that are able to interact differentially and to some degree separately with targets proteins. In addition, CaM can interact with and regulates several proteins that function exclusively as adaptors. This review provides an overview over our present knowledge concerning the structural and functional aspects of the role of CaM as an adaptor protein and as a regulator of known adaptor/scaffold proteins.
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Although chromosomal replication is an essential feature of the bacterial life cycle, the replication mechanism and involved molecular players have never been properly characterized in the Acetobacter genera. Thanks to whole-genom...
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Although chromosomal replication is an essential feature of the bacterial life cycle, the replication mechanism and involved molecular players have never been properly characterized in the Acetobacter genera. Thanks to whole-genome sequencing, the unknown replication proteins from Acetobacter pasteurianus and Acetobacter orleanensis, DnaA-like and DnaB-like, could be identified. Despite the low nucleotide or amino acid similarity to the respective orthologs from Escherichia coli, their involvement during replication regulation was corroborated by artificial microRNA. In the Acetobacter genome, a novel replication origin, oriAo, was detected with three 9-nucleotide-long DnaA boxes to which DnaA-like proteins bind actively. Bacterial two-hybrid systems and co-immunoprecipitation confirmed the homologous and heterologous interactions between DnaA-like and DnaB-like proteins with their E. coli orthologs. This communication is due to the conserved tryptophan at position 6 for E. coli or 25 for Acetobacter that unables DnaA-like proteins to form oligomeric protein structures after its substitution. Altogether, these results provide novel insights into the genome replication mechanism in Acetobacter. (C) 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.
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Abstract Protein structure docking is the process in which the quaternary structure of a protein complex is predicted from individual tertiary structures of the protein subunits. Protein docking is typically performed in two main ...
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Abstract Protein structure docking is the process in which the quaternary structure of a protein complex is predicted from individual tertiary structures of the protein subunits. Protein docking is typically performed in two main steps. The subunits are first docked while keeping them rigid to form the complex, which is then followed by structure refinement. Structure refinement is crucial for a practical use of computational protein docking models, as it is aimed for correcting conformations of interacting residues and atoms at the interface. Here, we benchmarked the performance of eight existing protein structure refinement methods in refinement of protein complex models. We show that the fraction of native contacts between subunits is by far the most straightforward metric to improve. However, backbone dependent metrics, based on the Root Mean Square Deviation proved more difficult to improve via refinement.
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