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Journal ArticleDOI

Native aggregation as a cause of origin of temporary cellular structures needed for all forms of cellular activity, signaling and transformations

09 Jun 2010-Theoretical Biology and Medical Modelling (BioMed Central)-Vol. 7, Iss: 1, pp 19-19
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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Citations
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Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
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 ArticleDOI
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

References
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Journal ArticleDOI
TL;DR: A new web-based tool for the prediction of protein phosphorylation sites, DISPHOS (DISorder-enhanced PHOSphorylation predictor, http://www.ist. edu/DISPHOS), which observes that amino acid compositions, sequence complexity, hydrophobicity, charge and other sequence attributes of regions adjacent to phosphate sites are very similar to those of intrinsically disordered protein regions.
Abstract: Reversible protein phosphorylation provides a major regulatory mechanism in eukaryotic cells. Due to the high variability of amino acid residues flanking a relatively limited number of experimentally identified phosphorylation sites, reliable prediction of such sites still remains an important issue. Here we report the development of a new web-based tool for the prediction of protein phosphorylation sites, DISPHOS (DISorder-enhanced PHOSphorylation predictor, http://www.ist.temple. edu/DISPHOS). We observed that amino acid compositions, sequence complexity, hydrophobicity, charge and other sequence attributes of regions adjacent to phosphorylation sites are very similar to those of intrinsically disordered protein regions. Thus, DISPHOS uses position-specific amino acid frequencies and disorder information to improve the discrimination between phosphorylation and non-phosphorylation sites. Based on the estimates of phosphorylation rates in various protein categories, the outputs of DISPHOS are adjusted in order to reduce the total number of misclassified residues. When tested on an equal number of phosphorylated and non-phosphorylated residues, the accuracy of DISPHOS reaches 76% for serine, 81% for threonine and 83% for tyrosine. The significant enrichment in disorder-promoting residues surrounding phosphorylation sites together with the results obtained by applying DISPHOS to various protein functional classes and proteomes, provide strong support for the hypothesis that protein phosphorylation predominantly occurs within intrinsically disordered protein regions.

1,307 citations


"Native aggregation as a cause of or..." refers background in this paper

  • ...For instance, analysis of amino acid sequences in the regions surrounding known phosphorylation sites reveals a strong propensity towards adoption of a natively unfolded conformation [31]....

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Journal ArticleDOI
TL;DR: The data suggest that intrinsically unstructured proteins play key roles in cell-signaling, regulation and cancer, where coupled folding and binding is a common mechanism.

1,156 citations


"Native aggregation as a cause of or..." refers background in this paper

  • ...At the same time, it has been shown in silico that the natively unfolded regions are more extensive in cancer cell proteins: in cancer-associated proteins, the number of such areas is 70% greater, while in signaling proteins it is 5 times greater [50]....

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Journal ArticleDOI
TL;DR: A number of new biophysical techniques are proving exceptionally useful in defining the limits of the conformational ensembles of intrinsically disordered proteins and are beginning to reveal general principles underlying their biological functions.

969 citations


"Native aggregation as a cause of or..." refers background in this paper

  • ...Most commonly, four stages of such interaction are identified: (i) random collision of natively unfolded protein with target; (ii) weak, nonspecific interaction of natively unfolded protein with target; (iii) formation of secondary structures in natively unfolded protein; (iv) owing to these nascent secondary structures, a firm complex of the natively unfolded protein with the protein-target is formed [37,38]....

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Journal ArticleDOI
TL;DR: The results suggest that a satisfactory bioequivalence (BE) test for more than 55% of the high-solubility Class 1 and Class 3 drug products on the WHO Essential Drug List may be based on an in vitro dissolution test.
Abstract: The purpose of this study is to provisionally classify, based on the Biopharmaceutics Classification System (BCS), drugs in immediate-release dosage forms that appear on the World Health Organization (WHO) Essential Drug List. The classification in this report is based on the aqueous solubility of the drugs reported in commonly available reference literature and a correlation of human intestinal membrane permeability for a set of 29 reference drugs with their calculated partition coefficients. The WHO Essential Drug List consists of a total of 325 medicines and 260 drugs, of which 123 are oral drugs in immediate-release (IR) products. Drugs with dose numbers less than or equal to unity [Do = (maximum dose strength/250 mL)/solubility ≤ 1] are defined as high-solubility drugs. Drug solubility for the uncharged, lowest-solubility form reported in the Merck Index or USP was used. Of the 123 WHO oral drugs in immediate-release dosage forms, 67% (82) were determined to be high-solubility drugs. The classificati...

811 citations


"Native aggregation as a cause of or..." refers background in this paper

  • ...This hydrophobic compound [52] scarcely affects the nor-...

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