Recognition between flexible protein molecules: induced and assisted folding

Demchenko, Alexander P.

doi:10.1002/1099-1352(200101/02)14:1<42::aid-jmr518>3.0.co;2-8

Cited by 159 publications

(102 citation statements)

References 238 publications

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“…Our present result is also an example where small ions by preferential interaction to a protein at its unstructured N-terminal part signals conformational changes in the structured region of the protein situated at a distance from the site of interaction. Similar instances are known for protein-protein and protein-nucleic acid interactions which produce conformational signal transduction at a substantial distance from the sites of interaction of the molecules (53). However, a detailed study of the behavior of prion protein in various salt solutions in different environmental conditions, viz., pH, would be useful for understanding the process of unfolding of the molecule.…”

Section: Discussionmentioning

confidence: 88%

Unusual Property of Prion Protein Unfolding in Neutral Salt Solution

2002

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The unfolding of cellular prion protein and its refolding to the scrapie isoform are related to prion diseases. Studies in the literature have shown that structures of proteins, either acidic or basic, are stabilized against denaturation by certain neutral salts, for example, sulfate and fluoride. Contrary to these observations, the full-length recombinant prion protein (amino acid residues 23-231) is denatured by these protein structure stabilizing salts. Under identical concentrations of salts, the structure of the sheep prion protein, which contains a greater number of glycine groups in the N-terminal unstructured segment than the mouse protein, becomes more destabilized. In contrast to the full-length protein, the C-terminal 121-231 prion protein fragment, consisting of all the structural elements of the protein, viz., three R-helices and two short -strands, is stabilized against denaturation by these salts. We suggest that an increase in the concentration of the anions on the surface of the prion protein molecule due to their preferential interaction with the glycine residues in the N-terminal segment destabilizes the structure of the prion protein by perturbing the prion helix 1 which is the most soluble of all the protein R-helices reported so far in the literature. The present results could be relevant to explain the observed structural conversion of the prion protein by anionic nucleic acids and sulfated glycosaminoglycans.

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Section: Discussionmentioning

confidence: 88%

Unusual Property of Prion Protein Unfolding in Neutral Salt Solution

2002

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“…Arguably, splicing within a structured protein domain would have catastrophic effects on the structure of the remaining protein (9), leading to misfolding and aggregation. Fig.…”

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confidence: 99%

Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms

Romero

Zaidi

Fang

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

435

387

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Alternative splicing of pre-mRNA generates two or more protein isoforms from a single gene, thereby contributing to protein diversity. Despite intensive efforts, an understanding of the protein structure-function implications of alternative splicing is still lacking. Intrinsic disorder, which is a lack of equilibrium 3D structure under physiological conditions, may provide this understanding. Intrinsic disorder is a common phenomenon, particularly in multicellular eukaryotes, and is responsible for important protein functions including regulation and signaling. We hypothesize that polypeptide segments affected by alternative splicing are most often intrinsically disordered such that alternative splicing enables functional and regulatory diversity while avoiding structural complications. We analyzed a set of 46 differentially spliced genes encoding experimentally characterized human proteins containing both structured and intrinsically disordered amino acid segments. We show that 81% of 75 alternatively spliced fragments in these proteins were associated with fully (57%) or partially (24%) disordered protein regions. Regions affected by alternative splicing were significantly biased toward encoding disordered residues, with a vanishingly small P value. A larger data set composed of 558 SwissProt proteins with known isoforms produced by 1,266 alternatively spliced fragments was characterized by applying the PONDR VSL1 disorder predictor. Results from prediction data are consistent with those obtained from experimental data, further supporting the proposed hypothesis. Associating alternative splicing with protein disorder enables the time-and tissue-specific modulation of protein function needed for cell differentiation and the evolution of multicellular organisms.evolution ͉ natively unfolded ͉ intrinsically unstructured ͉ protein structure T he splicing of pre-mRNA (1) was first described in 1977. Soon thereafter, Gilbert (2) coined the terms ''intron'' (intragenic region) and ''exon'' (expressed region) for the noncoding and coding regions, respectively. Alternative splicing occurs when different mRNAs are assembled from a single gene by joining exons in different ways. Alternative splicing is proposed to generate complexity in multicellular eukaryotes by increasing protein diversity, and thus proteome size, from a relatively small number of genes (3). Estimates indicate that between 35 and 60% of human genes yield protein isoforms by means of alternatively spliced (AS) mRNA (4). Furthermore, complexity in higher organisms is also brought about by signaling and regulatory networks that enable robustness (5). The importance of alternative splicing as a regulatory process (3, 6) has been highlighted by the high occurrence of such splicing in the pre-mRNAs of regulatory and signaling proteins (7).Alternative splicing can bolster organism complexity, not only by effectively increasing proteome size and regulatory and signaling network complexity, but also by doing so in a time-and tissue-specific manner, supporting ...

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“…Structural complexity of biological macromolecules allows for a large variety of mechanisms to regulate the molecular recognition, including key-lock binding, template-assisted folding, folding by association, conformational selection, etc. Whether the recognition involves inducible or constitutive binding, the interaction per se depends on and affects the secondary structure of the individual protein (43)(44)(45)(46)(47). It seems reasonable therefore to analyze the deviation of the secondary structure (assigned by crystallography and NMR data) in various protein families with specific emphasis on the residues embedded in configurations with high flexibility.…”

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confidence: 99%

Local Flexibility in Molecular Function Paradigm

Bhalla

Storchan

MacCarthy

et al. 2006

Molecular & Cellular Proteomics

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It is generally accepted that the functional activity of biological macromolecules requires tightly packed three-dimensional structures. Recent theoretical and experimental evidence indicates, however, the importance of molecular flexibility for the proper functioning of some proteins. We examined high resolution structures of proteins in various functional categories with respect to the secondary structure assessment. The latter was considered as a characteristic of the inherent flexibility of a polypeptide chain. We found that the proteins in functionally competent conformational states might be comprised of 20 -70% flexible residues. For instance, proteins involved in gene regulation, e.g. transcription factors, are on average largely disordered molecules with over 60% of amino acids residing in "coiled" configurations. In contrast, oxygen transporters constitute a class of relatively rigid molecules with only 30% of residues being locally flexible.

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Recognition between flexible protein molecules: induced and assisted folding

Cited by 159 publications

References 238 publications

Unusual Property of Prion Protein Unfolding in Neutral Salt Solution

Unusual Property of Prion Protein Unfolding in Neutral Salt Solution

Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms

Local Flexibility in Molecular Function Paradigm

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