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Franz X Schmid - One of the best experts on this subject based on the ideXlab platform.
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chaperone domains convert prolyl isomerases into generic catalysts of Protein Folding
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Roman P Jakob, Gabriel Zoldak, Tobias Aumuller, Franz X SchmidAbstract:The cis/trans isomerization of peptide bonds before proline (prolyl bonds) is a rate-limiting step in many Protein Folding reactions, and it is used to switch between alternate functional states of folded Proteins. Several prolyl isomerases of the FK506-binding Protein family, such as trigger factor, SlyD, and FkpA, contain chaperone domains and are assumed to assist Protein Folding in vivo. The prolyl isomerase activity of FK506-binding Proteins strongly depends on the nature of residue Xaa of the Xaa-Pro bond. We confirmed this in assays with a library of tetrapeptides in which position Xaa was occupied by all 20 aa. A high sequence specificity seems inconsistent with a generic function of prolyl isomerases in Protein Folding. Accordingly, we constructed a library of Protein variants with all 20 aa at position Xaa before a rate-limiting cis proline and used it to investigate the performance of trigger factor and SlyD as catalysts of proline-limited Folding. The efficiencies of both prolyl isomerases were higher than in the tetrapeptide assays, and, intriguingly, this high activity was almost independent of the nature of the residue before the proline. Apparently, the almost indiscriminate binding of the chaperone domain to the reFolding Protein chain overrides the inherently high sequence specificity of the prolyl isomerase site. The catalytic performance of these Folding enzymes is thus determined by generic substrate recognition at the chaperone domain and efficient transfer to the active site in the prolyl isomerase domain.
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Protein Folding prolyl isomerases join the fold
Current Biology, 1995Co-Authors: Franz X SchmidAbstract:Cyclophilins have prolyl isomerase activity, but evidence for their suggested role in Protein Folding in cells has been scarce; now they have been found to accelerate the Folding of mitochondrial precursor Proteins.
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prolyl isomerase enzymatic catalysis of slow Protein Folding reactions
Annual Review of Biophysics and Biomolecular Structure, 1993Co-Authors: Franz X SchmidAbstract:PROLYL ISOMERIZATION . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Isomerization 0/ Peptide Bonds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Prolyllsomerizations in Protein Folding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . 126
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catalysis of Protein Folding by cyclophilins from different species
Journal of Biological Chemistry, 1991Co-Authors: Erhard Ralf Schonbrunner, Gunter Fischer, Sabine Mayer, Maximilian Tropschug, Nobuhiro Takahashi, Franz X SchmidAbstract:Cyclophilins are a class of ubiquitous Proteins with yet unknown function. They were originally discovered as the major binding Proteins for the immunosuppressant cyclosporin A. The only known catalytic function of these Proteins in vitro is the cis/trans isomerization of Xaa-Pro bonds in oligopeptides. This became clear after the discovery that bovine cyclophilin is identical with porcine prolyl isomerase. This enzyme accelerates slow, proline-limited steps in the reFolding of several Proteins. Here we demonstrate that the cyclophilins from man, pig, Neurospora crassa, Saccharomyces cerevisiae, and Escherichia coli are all active as prolyl isomerases and as catalysts of Protein Folding. This evolutionary conservation suggests that catalysis of prolyl peptide bond isomerization may be an important function of the cyclophilins. It could be related with de novo Protein Folding or be involved in regulatory processes. Catalysis of Folding is very efficient in the presence of the high cellular concentrations of prolyl isomerase.
Eugene I Shakhnovich - One of the best experts on this subject based on the ideXlab platform.
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Protein Folding thermodynamics and dynamics where physics chemistry and biology meet
Chemical Reviews, 2006Co-Authors: Eugene I ShakhnovichAbstract:As was noted in our recent review 1 the Protein Folding field underwent a cyclic development. Initially Protein Folding was viewed as a strictly experimental field belonging to realm of biochemistry where each Protein is viewed as a unique system that requires its own detailed characterization – akin to any mechanism in biology. The theoretical thinking at this stage of development of the field was dominated by the quest to solve so-called “Levinthal paradox” that posits that a Protein could not find its native conformation by exhaustive random search. Introduction, in the early nineties, of simplified models to the Protein Folding field and their success in explaining several key aspects of Protein Folding, such as two-state Folding of many Proteins, the nucleation mechanism and its relation to native state topology, have pretty much shifted thinking towards views inspired by physics. The “physics”-centered approach focuses on statistical mechanical aspect of the Folding problem by emphasizing universality of Folding scenarios over the uniqueness of Folding pathways for each Protein. Its main achievement is a solution of the Protein Folding problem in principle, i.e. demonstration how Proteins could fold. As a result, a “psychological” solution of the Levinthal paradox was found (i.e. it was generally understood that this is not a paradox. after all). The key success of this stage of the field is discovery of the general requirements for polypeptide sequences to be cooperatively foldable stable Proteins and realization that such requirements can be achieved by sequence selection. That put the field strongly into the realm of biology (“Nothing in Biology makes sense except in the light of Evolution” (Theodosius Dobzhansky)) The physics-based fundamental approach to Protein Folding dominated theoretical thinking in the last decade (reviewed in 1-4) and its successes brought theory and experiment closer together At the present stage we seek better understanding of how Protein Folding problem is actually solved in Nature. In this sense the Protein Folding field has made a full circle as attention is again focused on specific Proteins and details of their Folding mechanism. However these questions are asked at a new level of sophistication of both theory and experiment. Understanding of general principles of Folding and vastly improved computer power makes it possible to develop tractable models that sometimes achieve atomic level of accuracy. Further, better general understanding of requirement for polypeptide sequences to fold, lead to establishment of direct links between Protein Folding and evolution of their sequences This development opened an opportunity to employ powerful methods of bioinformatics to test predictions of various Folding models, in addition to more traditional tests of models against experiment After all, evolution presents a giant natural laboratory where sequences are designed to fold and function and availability of vast amounts of data certainly calls for its use to better understand Folding of Proteins at very high resolution. At the same time in vitro experimental approaches progressed to the point that very accurate time- and structure- resolved data are available. A close interaction with experimentalists helps to keep theorists honest by providing detailed tests of theories and simulation results. In this review, which to a great extent reflects the thinking of the author on the subject, we will first summarize basic questions and present simple, coarse-grained models that provide a basis for a fundamental understanding of Protein Folding thermodynamics and kinetics. Then we will discuss more recent developments (over last five years) that focus on detailed studies of Folding mechanisms of specific Proteins, and finally we will briefly discuss some outstanding questions and future directions.
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Protein Folding theory from lattice to all atom models
Annual Review of Biophysics and Biomolecular Structure, 2001Co-Authors: Leonid A Mirny, Eugene I ShakhnovichAbstract:▪ Abstract This review focuses on recent advances in understanding Protein Folding kinetics in the context of nucleation theory. We present basic concepts such as nucleation, Folding nucleus, and transition state ensemble and then discuss recent advances and challenges in theoretical understanding of several key aspects of Protein Folding kinetics. We cover recent topology-based approaches as well as evolutionary studies and molecular dynamics approaches to determine Protein Folding nucleus and analyze other aspects of Folding kinetics. Finally, we briefly discuss successful all-atom Monte-Carlo simulations of Protein Folding and conclude with a brief outlook for the future.
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identifying the Protein Folding nucleus using molecular dynamics
Journal of Molecular Biology, 2000Co-Authors: Sergey V Buldyrev, Nikolay V Dokholyan, Eugene H Stanley, Eugene I ShakhnovichAbstract:Molecular dynamics simulations of Folding in an off-lattice Protein model reveal a nucleation scenario, in which a few well-defined contacts are formed with high probability in the transition state ensemble of conformations. Their appearance determines Folding cooperativity and drives the model Protein into its folded conformation. Amino acid residues participating in those contacts may serve as "accelerator pedals" used by molecular evolution to control Protein Folding rate.
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on the transition coordinate for Protein Folding
APS March Meeting Abstracts, 1998Co-Authors: Vijay S Pande, Alexander Y Grosberg, Toyoichi Tanaka, Eugene I ShakhnovichAbstract:To understand the kinetics of Protein Folding, we introduce the concept of a “transition coordinate” which is defined to be the coordinate along which the system progresses most slowly. As a practical implementation of this concept, we define the transmission coefficient for any conformation to be the probability for a chain with the given conformation to fold before it unfolds. Since the transmission coefficient can serve as the best possible measure of kinetic distance for a system, we present two methods by which we can determine how closely any parameter of the system approximates the transmission coefficient. As we determine that the transmission coefficient for a short-chain heteropolymer system is dominated by entropic factors, we have chosen to illustrate the methods mentioned by applying them to geometrical properties of the system such as the number of native contacts and the looplength distribution. We find that these coordinates are not good approximations of the transmission coefficient and therefore, cannot adequately describe the kinetics of Protein Folding.
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theoretical studies of Protein Folding thermodynamics and kinetics
Current Opinion in Structural Biology, 1997Co-Authors: Eugene I ShakhnovichAbstract:Abstract Recently, Protein-Folding models have advanced to the point where Folding simulations of Protein-like chains of reasonable length (up to 125 amino acids) are feasible, and the major physical features of Folding Proteins, such as cooperativity in thermodynamics and nucleation mechanisms in kinetics, can be reproduced. This has allowed deep insight into the physical mechanism of Folding, including the solution of the so-called ‘Levinthal paradox’.
David Baker - One of the best experts on this subject based on the ideXlab platform.
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computer based redesign of a Protein Folding pathway
Nature Structural & Molecular Biology, 2001Co-Authors: Sehat Nauli, Brian Kuhlman, David BakerAbstract:A fundamental test of our current understanding of Protein Folding is to rationally redesign Protein Folding pathways. We use a computer-based design strategy to switch the Folding pathway of Protein G, which normally involves formation of the second, but not the first, beta-turn at the rate limiting step in Folding. Backbone conformations and amino acid sequences that maximize the interaction density in the first beta-hairpin were identified, and two variants containing 11 amino acid replacements were found to be approximately 4 kcal mol-1 more stable than wild type Protein G. Kinetic studies show that the redesigned Proteins fold approximately 100 x faster than wild type Protein and that the first beta-turn is formed and the second disrupted at the rate limiting step in Folding.
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mechanisms of Protein Folding
Current Opinion in Structural Biology, 2001Co-Authors: Viara P Grantcharova, David Baker, Eric J Alm, Arthur L HorwichAbstract:The strong correlation between Protein Folding rates and the contact order suggests that Folding rates are largely determined by the topology of the native structure. However, for a given topology, there may be several possible low free energy paths to the native state and the path that is chosen (the lowest free energy path) may depend on differences in interaction energies and local free energies of ordering in different parts of the structure. For larger Proteins whose Folding is assisted by chaperones, such as the Escherichia coli chaperonin GroEL, advances have been made in understanding both the aspects of an unfolded Protein that GroEL recognizes and the mode of binding to the chaperonin. The possibility that GroEL can remove non-native Proteins from kinetic traps by unFolding them either during polypeptide binding to the chaperonin or during the subsequent ATP-dependent formation of Folding-active complexes with the co-chaperonin GroES has also been explored.
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a surprising simplicity to Protein Folding
Nature, 2000Co-Authors: David BakerAbstract:The polypeptide chains that make up Proteins have thousands of atoms and hence millions of possible inter-atomic interactions. It might be supposed that the resulting complexity would make prediction of Protein structure and Protein-Folding mechanisms nearly impossible. But the fundamental physics underlying Folding may be much simpler than this complexity would lead us to expect: Folding rates and mechanisms appear to be largely determined by the topology of the native (folded) state, and new methods have shown great promise in predicting Protein-Folding mechanisms and the three-dimensional structures of Proteins.
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prediction of Protein Folding mechanisms from free energy landscapes derived from native structures
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: David BakerAbstract:Guided by recent experimental results suggesting that Protein-Folding rates and mechanisms are determined largely by native-state topology, we develop a simple model for Protein Folding free-energy landscapes based on native-state structures. The configurations considered by the model contain one or two contiguous stretches of residues ordered as in the native structure with all other residues completely disordered; the free energy of each configuration is the difference between the entropic cost of ordering the residues, which depends on the total number of residues ordered and the length of the loop between the two ordered segments, and the favorable attractive interactions, which are taken to be proportional to the total surface area buried by the ordered residues in the native structure. Folding kinetics are modeled by allowing only one residue to become ordered/disordered at a time, and a rigorous and exact method is used to identify free-energy maxima on the lowest free-energy paths connecting the fully disordered and fully ordered configurations. The distribution of structure in these free-energy maxima, which comprise the transition-state ensemble in the model, are reasonably consistent with experimental data on the Folding transition state for five of seven Proteins studied. Thus, the model appears to capture, at least in part, the basic physics underlying Protein Folding and the aspects of native-state topology that determine Protein-Folding mechanisms.
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kinetics versus thermodynamics in Protein Folding
Biochemistry, 1994Co-Authors: David Baker, David A AgardAbstract:Until quite recently it has been generally believed that the observed tertiary structure of a Protein is controlled by thermodynamic and not kinetic processes. In this essay we review several recent results which call into question the universality of the thermodynamic hypothesis and discuss their implications for the understanding of Protein Folding.
Vijay S Pande - One of the best experts on this subject based on the ideXlab platform.
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simple few state models reveal hidden complexity in Protein Folding
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Kyle A Beauchamp, Robert T Mcgibbon, Yushan Lin, Vijay S PandeAbstract:Markov state models constructed from molecular dynamics simulations have recently shown success at modeling Protein Folding kinetics. Here we introduce two methods, flux PCCA+ (FPCCA+) and sliding constraint rate estimation (SCRE), that allow accurate rate models from Protein Folding simulations. We apply these techniques to fourteen massive simulation datasets generated by Anton and Folding@home. Our protocol quantitatively identifies the suitability of describing each system using two-state kinetics and predicts experimentally detectable deviations from two-state behavior. An analysis of the villin headpiece and FiP35 WW domain detects multiple native substates that are consistent with experimental data. Applying the same protocol to GTT, NTL9, and Protein G suggests that some beta containing Proteins can form long-lived native-like states with small register shifts. Even the simplest Protein systems show Folding and functional dynamics involving three or more states.
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solvent viscosity dependence of the Protein Folding dynamics
Journal of Physical Chemistry B, 2008Co-Authors: Young Min Rhee, Vijay S PandeAbstract:Solvent viscosity has been frequently adopted as an adjustable parameter in various computational studies (e.g., Protein Folding simulations) with implicit solvent models. A common approach is to use low viscosities to expedite simulations. While using viscosities lower than that of aqueous is unphysical, such treatment is based on observations that the viscosity affects the kinetics (rates) in a well-defined manner as described by Kramers' theory. Here, we investigate the effect of viscosity on the detailed dynamics (mechanism) of Protein Folding. On the basis of a simple mathematical model, we first show that viscosity may indeed affect the dynamics in a complex way. By applying the model to the Folding of a small Protein, we demonstrate that the detailed dynamics is affected rather pronouncedly especially at unphysically low viscosities, cautioning against using such viscosities. In this regard, our model may also serve as a diagnostic tool for validating low-viscosity simulations. It is also suggested...
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on the transition coordinate for Protein Folding
APS March Meeting Abstracts, 1998Co-Authors: Vijay S Pande, Alexander Y Grosberg, Toyoichi Tanaka, Eugene I ShakhnovichAbstract:To understand the kinetics of Protein Folding, we introduce the concept of a “transition coordinate” which is defined to be the coordinate along which the system progresses most slowly. As a practical implementation of this concept, we define the transmission coefficient for any conformation to be the probability for a chain with the given conformation to fold before it unfolds. Since the transmission coefficient can serve as the best possible measure of kinetic distance for a system, we present two methods by which we can determine how closely any parameter of the system approximates the transmission coefficient. As we determine that the transmission coefficient for a short-chain heteropolymer system is dominated by entropic factors, we have chosen to illustrate the methods mentioned by applying them to geometrical properties of the system such as the number of native contacts and the looplength distribution. We find that these coordinates are not good approximations of the transmission coefficient and therefore, cannot adequately describe the kinetics of Protein Folding.
Ulrich F Hartl - One of the best experts on this subject based on the ideXlab platform.
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in vivo aspects of Protein Folding and quality control
Science, 2016Co-Authors: David Balchin, Manajit Hayerhartl, Ulrich F HartlAbstract:BACKGROUND Proteins are synthesized on ribosomes as linear chains of amino acids and must fold into unique three-dimensional structures to fulfill their biological functions. Protein Folding is intrinsically error-prone, and how it is accomplished efficiently represents a problem of great biological and medical importance. During Folding, the nascent polypeptide must navigate a complex energy landscape. As a result, misfolded molecules may accumulate that expose hydrophobic amino acid residues and thus are in danger of forming potentially toxic aggregates. To ensure efficient Folding and prevent aggregation, cells in all domains of life express various classes of Proteins called molecular chaperones. These Proteins receive the nascent polypeptide chain emerging from the ribosome and guide it along a productive Folding pathway. Because Proteins are structurally dynamic, constant surveillance of the proteome by an integrated network of chaperones and Protein degradation machineries, the proteostasis network (PN), is required to maintain Protein homeostasis in a range of external and endogenous stress conditions. ADVANCES Over the past decade, we have gained substantial new insight into the overall behavior of the PN and the molecular mechanics of its components. Advances in structural biology and biophysical approaches have allowed chaperone mechanisms to be interrogated at an unprecedented level of detail. Recent work has provided fascinating insight into the process of Protein Folding on the ribosome and revealed how highly allosteric chaperones such as the heat shock Protein 70 (Hsp70), Hsp90, and chaperonin systems modulate the Folding energy landscapes of their Protein clients. Studies of chaperone systems from bacteria and eukaryotes have revealed common principles underlying the organization of chaperone networks in different domains of life. Recently, we have begun to appreciate the relative complexity of eukaryotic chaperones and are starting to understand how eukaryotes deal with the challenge of Folding a large proteome enriched in multidomain Proteins. At the cellular level, the response of the PN to conformational stress, aging, and diseases of aberrant Protein Folding has been an area of intense investigation. Importantly, the capacity of the PN declines during aging and this leads to dysfunction of specific cell types and tissues, rendering the organism susceptible to chronic diseases. Among these, neurodegenerative syndromes associated with Protein aggregation are increasingly prevalent in the aging human population. Notably, the accumulation of toxic Protein aggregates is both a consequence and a cause of PN decline, driving a vicious cycle that ultimately leads to proteostasis collapse. OUTLOOK A new view of Protein Folding is emerging, whereby the energy landscapes that Proteins navigate during Folding in vivo may differ substantially from those observed during reFolding in vitro. From the ribosome through to the major chaperone systems, the nascent Protein interacts with factors that modulate its Folding pathway. Future work should focus on obtaining the high-resolution structural and kinetic information necessary to define the pathways of Protein Folding during translation, and in association with molecular chaperones. Organisms have evolved various mechanisms to deal with misfolded and aggregated Proteins to maintain proteostasis. It is becoming increasingly clear that besides removing these Proteins by degradation, cells also strategically sequester them into transient or stable aggregates, often in defined cellular locations. Much remains to be understood about how this cellular decision-making occurs at a molecular level and how dysregulation of these mechanisms leads to proteotoxicity. From a medical perspective, the intimate relationship between proteostasis and disease, aging, and neurodegeneration makes components of the PN logical drug targets, with the goal of promoting healthy aging. Pharmacological manipulation of the PN will require a detailed understanding of how the network responds to perturbation and how its different components cooperate.
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the groel groes chaperonin machine a nano cage for Protein Folding
Trends in Biochemical Sciences, 2016Co-Authors: Manajit Hayerhartl, Astrid Bracher, Ulrich F HartlAbstract:The bacterial chaperonin GroEL and its cofactor GroES constitute the paradigmatic molecular machine of Protein Folding. GroEL is a large double-ring cylinder with ATPase activity that binds non-native substrate Protein (SP) via hydrophobic residues exposed towards the ring center. Binding of the lid-shaped GroES to GroEL displaces the bound Protein into an enlarged chamber, allowing Folding to occur unimpaired by aggregation. GroES and SP undergo cycles of binding and release, regulated allosterically by the GroEL ATPase. Recent structural and functional studies are providing insights into how the physical environment of the chaperonin cage actively promotes Protein Folding, in addition to preventing aggregation. Here, we review different models of chaperonin action and discuss issues of current debate.
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molecular chaperone functions in Protein Folding and proteostasis
Annual Review of Biochemistry, 2013Co-Authors: Yujin E Kim, Manajit Hayerhartl, Astrid Bracher, Mark S Hipp, Ulrich F HartlAbstract:The biological functions of Proteins are governed by their three-dimensional fold. Protein Folding, maintenance of proteome integrity, and Protein homeostasis (proteostasis) critically depend on a complex network of molecular chaperones. Disruption of proteostasis is implicated in aging and the pathogenesis of numerous degenerative diseases. In the cytosol, different classes of molecular chaperones cooperate in evolutionarily conserved Folding pathways. Nascent polypeptides interact cotranslationally with a first set of chaperones, including trigger factor and the Hsp70 system, which prevent premature (mis)Folding. Folding occurs upon controlled release of newly synthesized Proteins from these factors or after transfer to downstream chaperones such as the chaperonins. Chaperonins are large, cylindrical complexes that provide a central compartment for a single Protein chain to fold unimpaired by aggregation. This review focuses on recent advances in understanding the mechanisms of chaperone action in promoting and regulating Protein Folding and on the pathological consequences of Protein misFolding and aggregation.
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hsp90 a specialized but essential Protein Folding tool
Journal of Cell Biology, 2001Co-Authors: Jason C Young, Ismail Moarefi, Ulrich F HartlAbstract:Hsp90 is unique among molecular chaperones. The majority of its known substrates are signal transduction Proteins, and recent work indicates that it uses a novel Protein-Folding strategy.
