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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TL;DR: Low molecular-weight metabolites (LMWMs) as discussed by the authors comprise primary or central and a plethora of intermediary or secondary metabolites, all of which are characterized by a molecular weight below 900 Dalton.
Abstract: Low-molecular-weight metabolites (LMWMs) comprise primary or central and a plethora of intermediary or secondary metabolites, all of which are characterized by a molecular weight below 900 Dalton. The latter are especially prominent in sessile higher organisms, such as plants, corals, sponges and fungi, but are produced by all types of microbial organisms too. Common to all of these carbon molecules are oxygen, nitrogen and, to a lesser extent, sulfur, as heteroatoms. The latter can contribute as electron donators or acceptors to cellular redox chemistry and define the potential of the molecule to enter charge-transfer complexes. Furthermore, they allow LMWMs to serve as organic ligands in coordination complexes of various inorganic metals as central atoms. Especially the transition metals Fe, Cu and Mn can catalyze one electron reduction of molecular oxygen, which results in formation of free radical species and reactive follow-up reaction products. As antioxidants LMWMs can scavenge free radicals. Depending on the chemical environment, the same LMWMs can act as pro-oxidants by reducing molecular oxygen. The cellular regulation of redox homeostasis, a balance between oxidation and reduction, is still far from being understood. Charge-transfer and coordination complex formation with metals shapes LMWMs into gel-like matrices in the cytosol. The quasi-polymer structure is lost usually during the isolation procedure. In the gel state, LMWMs possess semiconductor properties. Also proteins and membranes are semiconductors. Together they can represent biotransistor components that can be part of a chemoelectrical signaling system that coordinates systems chemistry by initiating cell differentiation or tissue homeostasis, the activated and the resting cell state, when it is required. This concept is not new and dates back to Albert Szent-Gyorgyi.
30 citations
TL;DR: The evidence is given that the first protocells may have been formed on the basis of intrinsically disordered peptides, and available data on the similarity of the physical properties of cell models and living cells allow the Virchow's postulate to be rephrase as follows.
Abstract: Cell theory, as formulated by Theodor Schwann in 1839, introduced the idea that the cell is the main structural unit of living nature. Later, in solving the problem of cell multiplication, Rudolf Virchow expanded the cell theory with a postulate: all cells only arise from pre-existing cells. But what did the very first cell arise from? This paper proposes extending the Virchow's law by the assumption that between the nonliving protocell and the first living cell the continuity of fundamental physical properties (the principle of invariance of physical properties) is preserved. The protocell is understood here as a cell-shaped physical system on the basis of the self-organized biologically significant prebiotic macromolecules, primarily peptides, having a potential to transform into the living cell. Biophase is considered as the physical basis of the membraneless protocell, the internal environment of which is separated from the external environment due to the phase of adsorbed water. The evidence is given that the first protocells may have been formed on the basis of intrinsically disordered peptides. Data on the similarity of the physical properties of living cells and the following model systems are given: protein and artificial polymer solutions, coacervate droplets, and ion-exchange resin granules. Available data on the similarity of the physical properties of cell models and living cells allow us to rephrase the Virchow's postulate as follows: the physical properties of a living cell could only arise from pre-existing physical properties of the protocell.
25 citations
TL;DR: The ATP effect on protein aggregation was ambiguous: ATP alone had no effect on the protein’s thermal stability but it facilitated protein‘s destabilization in the presence of nitric oxide.
Abstract: Background and objective
Regulating protein function in the cell by small molecules, provide a rapid, reversible and tunable tool of metabolic control. However, due to its complexity the issue is poorly studied so far. The effects of small solutes on protein behavior can be studied by examining changes of protein secondary structure, in its hydrodynamic radius as well as its thermal aggregation. The study aim was to investigate effects of adenosine-5’-triphosphate (ATP), spermine NONOate (NO donor) as well as sodium/potassium ions on thermal aggregation of albumin and hemoglobin. To follow aggregation of the proteins, their diffusion coefficients were measured by quasi-elastic light scattering (QELS) at constant pH (7.4) in the presence of solutes over a temperature range from 25°C to 80°C.
18 citations
Cites background from "Native aggregation as a cause of or..."
...Discussion Protein aggregation plays an important role in the cellular biology and in many applications of protein science and medical engineering [28]....
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Journal Article•
17 citations
TL;DR: Ling's theory is a complete quantitative theory with corroborated equations for solute distribution, transport, cell potentials and osmotic behaviour and describing the cell's energy cycle and IDP's are involved in all this.
Abstract: The example of gelatine shows that extended proteins behave quite differently than globular ones: with water they form a gel. Historically the colloid view of protoplasm was discredited in favour of membrane-(pump)-theory (MPT), but unjustified. In his association-induction hypothesis Ling demonstrates that MPT is full of contradictions and that the colloid view has to be re-considered. In that case IDP's play a crucial role in this. What Ling calls the ‘living state’ consists of the unitary protoplasmic structure from which it was experimentally demonstrated that it can survive and keep Na+ and K+ concentrations without a delineating membrane. It consists of unfolded polypeptide chains whereby the repetitive backbone peptide groups orient and polarise many layers of water, in which Na+ and other solutes have reduced solubility and whereby the polypeptide β- and ϒ-carboxyl-groups adsorb K+. This ‘associated’ state is the resting state: a coherent high-energy low-entropy meta-stable state. It can be kept by adsorbed ATP (NTP) eventually for years without consumption of ATP as demonstrated by Clegg on Artemia embryo's. Stimuli can transform this state into a lower-energy higher-entropy action state with dissociation of ADP and Pi and newly synthesised ATP can reinstall it. Rest-to-action and action-to-rest were shown to be real phase-shifts. Ling's theory is a complete quantitative theory with corroborated equations for solute distribution, transport, cell potentials and osmotic behaviour and describing the cell's energy cycle. IDP's are involved in all this. The new view on IDP's leads to new insights on the origin of life.
17 citations
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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