Native aggregation as a cause of origin of temporary cellular structures needed for all forms of cellular activity, signaling and transformations
TL;DR: According to the hypothesis explored in this paper, native aggregation is genetically controlled (programmed) reversible aggregation that occurs when interacting proteins form new temporary structures through highly specific interactions.
Abstract: According to the hypothesis explored in this paper, native aggregation is genetically controlled (programmed) reversible aggregation that occurs when interacting proteins form new temporary structures through highly specific interactions. It is assumed that Anfinsen's dogma may be extended to protein aggregation: composition and amino acid sequence determine not only the secondary and tertiary structure of single protein, but also the structure of protein aggregates (associates). Cell function is considered as a transition between two states (two states model), the resting state and state of activity (this applies to the cell as a whole and to its individual structures). In the resting state, the key proteins are found in the following inactive forms: natively unfolded and globular. When the cell is activated, secondary structures appear in natively unfolded proteins (including unfolded regions in other proteins), and globular proteins begin to melt and their secondary structures become available for interaction with the secondary structures of other proteins. These temporary secondary structures provide a means for highly specific interactions between proteins. As a result, native aggregation creates temporary structures necessary for cell activity. "One of the principal objects of theoretical research in any department of knowledge is to find the point of view from which the subject appears in its greatest simplicity." Josiah Willard Gibbs (1839-1903)
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01 Jan 2017
TL;DR: Ling developed a complete colloid model for the living cell, with a whole set of experimentally approved new equations that are able to explain contemporary new physical data on the coherent behaviour of cells, whereas MPT is incompatible.
Abstract: Is a cell a colloid with distribution coefficients and adsorption coefficients as prime physical-chemical parameters allowing a negative-entropy-driven bio-energetic based on coherence, as first proposed by Schrodinger in 1944? or does a cell possess ordinary water with small solutes including K+ in solution, and delineated by a membrane in which ion-pumps are located, which continuously have to oppose passive leaks. The latter view, called ‘membrane-(pump)-theory (MPT) underscores all current physiology and cell biology, but is energetically impossible. MPT was disproved by Ling during the 60s and 70s but unfortunately this remained unknown. Ling developed a complete colloid model for the living cell, with a whole set of experimentally approved new equations. All basic tenets of his so-called ‘association-induction-hypothesis’ (AIH) are experimentally approved. In addition, his AIH is able to explain contemporary new physical data on the coherent behaviour of cells, whereas MPT is incompatible.
5 citations
Cites background from "Native aggregation as a cause of or..."
...In 2010 Matveev [22] unified the independent views of Ling and of Nasonov....
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01 Jan 2016
TL;DR: Concept of IDPs and native aggregation gave Protein Folding Problem (PFP) an entirely different dimension and challenged conventional view of protein folding in which native state of a protein is a well packed functional structure.
Abstract: Coded language of protein folding lies in its sequence. One needs to decode this language to get the proper information about the protein structure and function. To study protein folding one needs to know various hierarchical structures, such as primary, secondary, tertiary and quaternary structures, and the forces involved in the formation of those structures. Study of domain organization and local folding can provide valuable information about the overall structure and function of a protein. Both theoretical and empirical approaches are developed to understand this long standing problem of science. Several theories have been used to explain the folding of proteins. Prominent theories are Ramachandran plot, lattice theory, and energy landscape theory. Several models are also suggested to explain the folding mechanism: framework model, hydrophobic collapse, nucleation condensation model, and jig-saw model. Chou and Fasman proposed empirical prediction of protein conformation. In lab denaturation/renaturation experiments, H-exchange method, molecular dynamic and Monte-Carlo simulation methods, and NMR relaxation methods are very useful tools to examine this phenomenon. Progress in this field opens various possibilities and new avenues to explain the folding process. Most prominent among them is the discovery of intrinsically disorder proteins (IDPs). Discovery of intermediates, specially molten globule, allow us to reconsider the conventional view of two state model of protein folding as proposed by Anfinsen. Concept of IDPs and native aggregation gave Protein Folding Problem (PFP) an entirely different dimension and challenged conventional view of protein folding in which native state of a protein is a well packed functional structure. After about 50 years of research, we are still far away from a definite answer to one of the long standing problems in science. Although growing understanding in this area exposes us to the complexity of this process. Better understanding of this process enhances not only biochemical understanding, but helps us in designing better therapeutics based on these molecules.
3 citations
TL;DR: The fundamental physical properties of a phase of compartmentalization – a biophase – are discussed, which changes the physical state of any biomolecular system, from supramolecular and subcellular structures to the cell as a whole.
Abstract: Since the 1880s, the concept of compartmentalizing through membranes has taken a firm place in cell physiology and has defined the objects, methods, and goals of physiologists’ research for decades. A huge mass of biologists know about the important role of intra-membrane pumps, channels, and lipids, and various hypotheses about the origin of life often begin with explanations about how the lipid membrane occurred, without which it is impossible to imagine the origin of a living cell. Against this background, there was a dissonance of statements that there are membraneless organelles in the cell, the functions of which are rapidly expanding under our eyes. Physically, they are similar to coacervate droplets, which from time to time were used to explain the origin of life, and now the coacervates are being more and more often discussed when describing the physics of the nucleus and cytoplasm of modern cells. However, ideas about the coacervate nature of cytoplasm/protoplasm originated in the first half of the 19th Century, when the contents of cells were likened to jelly, but this approach gradually faded into the shadows. Nevertheless, limited research in this area continued and was completed in the form of a membraneless cell physiology. Now that the focus of attention has turned to membraneless compartmentalization, it’s time to remember the past. The sorption properties of proteins are the physical basis of membraneless cell because of water adsorbed by proteins changes the physical state of any biomolecular system, from supramolecular and subcellular structures to the cell as a whole. A thermodynamic aqueous phase is formed because adsorbed water does not mix with ordinary water and, in this cause, is separated from the surrounding solution in the form of a compartment. This article discusses the fundamental physical properties of such a phase – a biophase. As it turned out, the Meyer–Overton rule, which led to the idea of a lipid membrane, also applies to membraneless condensates.
2 citations
TL;DR: Investigation of effects of a nitric oxide donor, ATP and sodium/potassium environment on the dynamics of thermal unfolding of human hemoglobin shed more light on molecular mechanisms and biophysics involved in the regulation of protein activity by small solutes in the cell.
Abstract: Minor changes in protein structure induced by small organic and inorganic molecules can result in significant metabolic effects. The effects can be even more profound if the molecular players are chemically active and present in the cell in considerable amounts. The aim of our study was to investigate effects of a nitric oxide donor (spermine NONOate), ATP and sodium/potassium environment on the dynamics of thermal unfolding of human hemoglobin (Hb). The effect of these molecules was examined by means of circular dichroism spectrometry (CD) in the temperature range between 25°C and 70°C. The alpha-helical content of buffered hemoglobin samples (0.1 mg/ml) was estimated via ellipticity change measurements at a heating rate of 1°C/min. Major results were: 1) spermine NONOate persistently decreased the hemoglobin unfolding temperature T
u
irrespectively of the Na + /K + environment, 2) ATP instead increased the unfolding temperature by 3°C in both sodium-based and potassium-based buffers and 3) mutual effects of ATP and NO were strongly influenced by particular buffer ionic compositions. Moreover, the presence of potassium facilitated a partial unfolding of alpha-helical structures even at room temperature. The obtained data might shed more light on molecular mechanisms and biophysics involved in the regulation of protein activity by small solutes in the cell.
2 citations
Cites background from "Native aggregation as a cause of or..."
...Protein unfolding with subsequent aggregation plays a crucial role in biology and in many applications of protein science and medical engineering [30]....
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References
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TL;DR: Anfinsen as discussed by the authors provided a sketch of the rich history of research that provided the foundation for his work on protein folding and the Thermodynamic Hypothesis, and outlined potential avenues of current and future scientific exploration.
Abstract: Stanford Moore, William Stein, and Anfinsen were awarded the Nobel Prize in Chemistry in 1972 for \"their contribution
to the understanding of the connection between chemical structure and catalytic activity of the active center of the ribonuclease
molecule.\" In his Nobel Lecture, Anfinsen provided a sketch of the rich history of research that provided the foundation
for his work on protein folding and the \"Thermodynamic Hypothesis,\" and outlined potential avenues of current and
future scientific exploration.
6,520 citations
TL;DR: Positive results of crowding include enhancing the collapse of polypeptide chains into functional proteins, the assembly of oligomeric structures and the efficiency of action of some molecular chaperones and metabolic pathways.
2,104 citations
"Native aggregation as a cause of or..." refers background in this paper
...11), while the protein concentration in the cytoplasm reaches 200-400 mg/mL [39]....
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TL;DR: Results of this analysis showed that intrinsically unstructured proteins do not possess uniform structural properties, as expected for members of a single thermodynamic entity, and the Protein Quartet model, with function arising from four specific conformations (ordered forms, molten globule, premolten globules, and random coils) is discussed.
Abstract: The experimental material accumulated in the literature on the conformational behavior of intrinsically unstructured (natively unfolded) proteins was analyzed. Results of this analysis showed that these proteins do not possess uniform structural properties, as expected for members of a single thermodynamic entity. Rather, these proteins may be divided into two structurally different groups: intrinsic coils, and premolten globules. Proteins from the first group have hydrodynamic dimensions typical of random coils in poor solvent and do not possess any (or almost any) ordered secondary structure. Proteins from the second group are essentially more compact, exhibiting some amount of residual secondary structure, although they are still less dense than native or molten globule proteins. An important feature of the intrinsically unstructured proteins is that they undergo disorder–order transition during or prior to their biological function. In this respect, the Protein Quartet model, with function arising from four specific conformations (ordered forms, molten globules, premolten globules, and random coils) and transitions between any two of the states, is discussed.
1,750 citations
"Native aggregation as a cause of or..." refers background in this paper
...When the nucleus melts, the globules increase in volume by approximately 50% [36]; free volume appears and, concomitantly, turn isomerization also becomes possible....
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...Uversky [36] proposed to supplement this list with a fourth, relatively stable protein conformation - the premolten globule, which might be called the boiling globule, as in the coordinates of the unfolding reaction it follows the globule and molten globule and precedes the completely unfolded conformation....
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1,634 citations
Book•
15 Aug 2014TL;DR: The sequence-structure relationships indicate that disorder is an encoded property, and the predictions strongly suggest that proteins in nature are much richer in intrinsic disorder than are those in the Protein Data Bank.
Abstract: Proteins can exist in a trinity of structures: the ordered state, the molten globule, and the random coil. The five following examples suggest that native protein structure can correspond to any of the three states (not just the ordered state) and that protein function can arise from any of the three states and their transitions. (1) In a process that likely mimics infection, fd phage converts from the ordered into the disordered molten globular state. (2) Nucleosome hyperacetylation is crucial to DNA replication and transcription; this chemical modification greatly increases the net negative charge of the nucleosome core particle. We propose that the increased charge imbalance promotes its conversion to a much less rigid form. (3) Clusterin contains an ordered domain and also a native molten globular region. The molten globular domain likely functions as a proteinaceous detergent for cell remodeling and removal of apoptotic debris. (4) In a critical signaling event, a helix in calcineurin becomes bound and surrounded by calmodulin, thereby turning on calcineurin's serine/threonine phosphatase activity. Locating the calcineurin helix within a region of disorder is essential for enabling calmodulin to surround its target upon binding. (5) Calsequestrin regulates calcium levels in the sarcoplasmic reticulum by binding approximately 50 ions/molecule. Disordered polyanion tails at the carboxy terminus bind many of these calcium ions, perhaps without adopting a unique structure. In addition to these examples, we will discuss 16 more proteins with native disorder. These disordered regions include molecular recognition domains, protein folding inhibitors, flexible linkers, entropic springs, entropic clocks, and entropic bristles. Motivated by such examples of intrinsic disorder, we are studying the relationships between amino acid sequence and order/disorder, and from this information we are predicting intrinsic order/disorder from amino acid sequence. The sequence-structure relationships indicate that disorder is an encoded property, and the predictions strongly suggest that proteins in nature are much richer in intrinsic disorder than are those in the Protein Data Bank. Recent predictions on 29 genomes indicate that proteins from eucaryotes apparently have more intrinsic disorder than those from either bacteria or archaea, with typically > 30% of eucaryotic proteins having disordered regions of length > or = 50 consecutive residues.
1,557 citations