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Functional anthology of intrinsic disorder. 3. Ligands, post-translational modifications, and diseases associated with intrinsically disordered proteins."
- Journal of proteome research
, 2007
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Functional anthology of intrinsic disorder. 2. Cellular components, domains, technical terms, developmental processes, and coding sequence diversities correlated with long disordered regions
- J Proteome Res
, 2007
"... Biologically active proteins without stable ordered structure (i.e., intrinsically disordered proteins) are attracting increased attention. Functional repertoires of ordered and disordered proteins are very different, and the ability to differentiate whether a given function is associated with intri ..."
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Biologically active proteins without stable ordered structure (i.e., intrinsically disordered proteins) are attracting increased attention. Functional repertoires of ordered and disordered proteins are very different, and the ability to differentiate whether a given function is associated with intrinsic disorder or with a well-folded protein is crucial for modern protein science. However, there is a large gap between the number of proteins experimentally confirmed to be disordered and their actual number in nature. As a result, studies of functional properties of confirmed disordered proteins, while helpful in revealing the functional diversity of protein disorder, provide only a limited view. To overcome this problem, a bioinformatics approach for comprehensive study of functional roles of protein disorder was proposed
Unfoldomics of Human Genetic Diseases: Illustrative Examples of Ordered and Intrinsically Disordered Members of the Human Diseasome
"... Abstract: Intrinsically disordered proteins (IDPs) constitute a recently recognized realm of atypical biologically active proteins that lack stable structure under physiological conditions, but are commonly involved in such crucial cellular processes as regulation, recognition, signaling and control ..."
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Abstract: Intrinsically disordered proteins (IDPs) constitute a recently recognized realm of atypical biologically active proteins that lack stable structure under physiological conditions, but are commonly involved in such crucial cellular processes as regulation, recognition, signaling and control. IDPs are very common among proteins associated with various diseases. Recently, we performed a systematic bioinformatics analysis of the human diseasome, a network that linked the human disease phenome (which includes all the human genetic diseases) with the human disease genome (which contains
How Random are Intrinsically Disordered Proteins? A Small Angle Scattering Perspective
"... Abstract: While the crucial role of intrinsically disordered proteins (IDPs) in the cell cycle is now recognized, decipher-ing their molecular mode of action at the structural level still remains highly challenging and requires a combination of many biophysical approaches. Among them, small angle X- ..."
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Abstract: While the crucial role of intrinsically disordered proteins (IDPs) in the cell cycle is now recognized, decipher-ing their molecular mode of action at the structural level still remains highly challenging and requires a combination of many biophysical approaches. Among them, small angle X-ray scattering (SAXS) has been extremely successful in the last decade and has become an indispensable technique for addressing many of the fundamental questions regarding the activities of IDPs. After introducing some experimental issues specific to IDPs and in relation to the latest technical de-velopments, this article presents the interest of the theory of polymer physics to evaluate the flexibility of fully disordered proteins. The different strategies to obtain 3-dimensional models of IDPs, free in solution and associated in a complex, are then reviewed. Indeed, recent computational advances have made it possible to readily extract maximum information from the scattering curve with a special emphasis on highly flexible systems, such as multidomain proteins and IDPs. Further-more, integrated computational approaches now enable the generation of ensembles of conformers to translate the unique flexible characteristics of IDPs by taking into consideration the constraints of more and more various complementary ex-periment. In particular, a combination of SAXS with high-resolution techniques, such as x-ray crystallography and NMR, allows us to provide reliable models and to gain unique structural insights about the protein over multiple structural scales. The latest neutron scattering experiments also promise new advances in the study of the conformational changes of mac-romolecules involving more complex systems.
Z.: Unsupervised integration of multiple protein disorder predictors
- In: IEEE Int’l. Conf. Bioinformatics and Biomedicine
, 2010
"... Abstract—Studies of intrinsically disordered proteins that lack a stable tertiary structure but still have important biological functions critically rely on computational methods that predict this property based on sequence information. Although a number of fairly successful models for prediction of ..."
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Abstract—Studies of intrinsically disordered proteins that lack a stable tertiary structure but still have important biological functions critically rely on computational methods that predict this property based on sequence information. Although a number of fairly successful models for prediction of protein disorder were developed over the last decade, the quality of their predictions is limited by available cases of confirmed disorders. To more reliably estimate protein disorder from protein sequences, an iterative algorithm is proposed that integrates predictions of multiple disorder models without relying on any protein sequences with confirmed disorder annotation. The iterative method alternately provides the maximum a posterior (MAP) estimation of disorder prediction and the maximum-likelihood (ML) estimation of quality of multiple disorder predictors. Experiments on data used at the Critical Assessment of Techniques for Protein Structure Prediction (CASP7 and CASP8) have shown the effectiveness of the proposed algorithm. Keywords—protein structure; disorder prediction; meta predictor; unsupervised learning; iterative MAP-ML algorithm I.
www.mdpi.com/journal/ijms Novel Strategies for Drug Discovery Based on Intrinsically Disordered Proteins (IDPs)
, 2011
"... Abstract: Intrinsically disordered proteins (IDPs) are proteins that usually do not adopt well-defined native structures when isolated in solution under physiological conditions. Numerous IDPs have close relationships with human diseases such as tumor, Parkinson disease, Alzheimer disease, diabetes, ..."
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Abstract: Intrinsically disordered proteins (IDPs) are proteins that usually do not adopt well-defined native structures when isolated in solution under physiological conditions. Numerous IDPs have close relationships with human diseases such as tumor, Parkinson disease, Alzheimer disease, diabetes, and so on. These disease-associated IDPs commonly play principal roles in the disease-associated protein-protein interaction networks. Most of them in the disease datasets have more interactants and hence the size of the disease-associated IDPs interaction network is simultaneously increased. For example, the tumor suppressor protein p53 is an intrinsically disordered protein and also a hub protein in the p53 interaction network; α-synuclein, an intrinsically disordered protein involved in Parkinson diseases, is also a hub of the protein network. The disease-associated IDPs may provide potential targets for drugs modulating protein-protein interaction networks. Therefore, novel strategies for drug discovery based on IDPs are in the ascendant. It is dependent on the features of IDPs to develop the novel strategies. It is found out that IDPs have unique structural features such as high flexibility and random coil-like conformations which enable them to participate in both the ―one to many ‖ and ―many to one ‖ interaction.
Retro-MoRFs: Identifying Protein Binding Sites by Normal and Reverse Alignment and Intrinsic Disorder Prediction
, 2010
"... Abstract: Many cell functions in all living organisms rely on protein-based molecular recognition involving disorder-to-order transitions upon binding by molecular recognition features (MoRFs). A well accepted computational tool for identifying likely protein-protein interactions is sequence alignme ..."
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Abstract: Many cell functions in all living organisms rely on protein-based molecular recognition involving disorder-to-order transitions upon binding by molecular recognition features (MoRFs). A well accepted computational tool for identifying likely protein-protein interactions is sequence alignment. In this paper, we propose the combination of sequence alignment and disorder prediction as a tool to improve the confidence of identifying MoRF-based protein-protein interactions. The method of reverse sequence alignment is also rationalized here as a novel approach for finding additional interaction regions, leading to the concept of a retro-MoRF, which has the reversed sequence of an identified MoRF. The set of retro-MoRF binding partners likely overlap the partner-sets of the originally identified MoRFs. The high abundance of MoRF-containing intrinsically disordered proteins in nature suggests the possibility that the number of retro-MoRFs could likewise be very high. This hypothesis provides new grounds for exploring the mysteries of protein-protein interaction networks at the genome level. Keywords: reverse; retro; invert; alignment; intrinsic disorder; PONDR-RIBSInt. J. Mol. Sci. 2010, 11 3726 1.
Predicting the Energetics of Conformational Fluctuations in Proteins from Sequence: A Strategy for Profiling the Proteome
"... SUMMARY The abundance of dynamic and disordered regions in proteins suggests that structural determinants alone may not be sufficient to describe function. Instead, descriptors that account for the dynamic features of the energy landscape populated by the protein ensemble may be required. Here, we ..."
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SUMMARY The abundance of dynamic and disordered regions in proteins suggests that structural determinants alone may not be sufficient to describe function. Instead, descriptors that account for the dynamic features of the energy landscape populated by the protein ensemble may be required. Here, we show that the thermodynamics of the dynamical complexity that imparts biological function can be largely reconstructed using sequence information alone, allowing thermodynamic characterization of entire proteomes without the need for structural analysis. We show that this tool can be used to analyze conserved energetic signatures within classes of proteins, as well as to compare the thermodynamic character of different proteomes.
Review What Macromolecular Crowding Can Do to a Protein
, 2014
"... Abstract: The intracellular environment represents an extremely crowded milieu, with a limited amount of free water and an almost complete lack of unoccupied space. Obviously, slightly salted aqueous solutions containing low concentrations of a biomolecule of interest are too simplistic to mimic the ..."
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Abstract: The intracellular environment represents an extremely crowded milieu, with a limited amount of free water and an almost complete lack of unoccupied space. Obviously, slightly salted aqueous solutions containing low concentrations of a biomolecule of interest are too simplistic to mimic the “real life ” situation, where the biomolecule of interest scrambles and wades through the tightly packed crowd. In laboratory practice, such macromolecular crowding is typically mimicked by concentrated solutions of various polymers that serve as model “crowding agents”. Studies under these conditions revealed that macromolecular crowding might affect protein structure, folding, shape, conformational stability, binding of small molecules, enzymatic activity, protein-protein interactions, protein-nucleic acid interactions, and pathological aggregation. The goal of this review is
