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Computational prediction of intrinsic disorder in protein sequences dates back to late 1970 and has flourished in the last two decades. We provide a brief historical overview, and we review over 30 recent predictors of disorder. We are the first to also cover predictors of molecular functions of disorder, including 13 methods that focus on disordered linkers and disordered protein–protein, protein–RNA, and protein–DNA binding regions. We overview their predictive models, usability, and predictive performance. We highlight newest methods and predictors that offer strong predictive performance measured based on recent comparative assessments. We conclude that the modern predictors are relatively accurate, enjoy widespread use, and many of them are fast. Their predictions are conveniently accessible to the end users, via web servers and databases that store pre-computed predictions for millions of proteins. However, research into methods that predict many not yet addressed functions of intrinsic disorder remains an outstanding challenge.

Signaling pathways allow cells to detect and respond to a wide variety of chemical (e.g. Ca 2+ or chemokine proteins) and physical stimuli (e.g., sheer stress, light). Together, these pathways form an extensive communication network that regulates basic cell activities and coordinates the function of multiple cells or tissues. The process of cell signaling imposes many demands on the proteins that comprise these pathways, including the abilities to form active and inactive states, and to engage in multiple protein interactions. Furthermore, successful signaling often requires amplifying the signal, regulating or tuning the response to the signal, combining information sourced from multiple pathways, all while ensuring fidelity of the process. This sensitivity, adaptability, and tunability are possible, in part, due to the inclusion of intrinsically disordered regions in many proteins involved in cell signaling. The goal of this collection is to highlight the many roles of intrinsic disorder in cell signaling. Following an overview of resources that can be used to study intrinsically disordered proteins, this review highlights the critical role of intrinsically disordered proteins for signaling in widely diverse organisms (animals, plants, bacteria, fungi), in every category of cell signaling pathway (autocrine, juxtacrine, intracrine, paracrine, and endocrine) and at each stage (ligand, receptor, transducer, effector, terminator) in the cell signaling process. Thus, a cell signaling pathway cannot be fully described without understanding how intrinsically disordered protein regions contribute to its function. The ubiquitous presence of intrinsic disorder in different stages of diverse cell signaling pathways suggest that more mechanisms by which disorder modulates intra- and inter-cell signals remain to be discovered. Graphical abstract

[...]these proteins/regions, with their unique structural plasticity, conformational adaptability, ability to react quickly in response to changes in their environment, and their binding promiscuity, are abundantly involved in various signaling, regulation, and recognition processes, and play diverse roles in the modulation and control of the functions of their binding partners (Dyson and Wright, 2005; Oldfield et al., 2008; Uversky and Dunker, 2010; Cozzetto and Jones, 2013; Ferreon et al., 2013). [...]the biological activities of IDPs/IDPRs are under tight control and are regulated by means of extensive posttranslational modifications (PTMs), such as phosphorylation, acetylation, glycosylation (Collins et al., 2008; Uversky and Dunker, 2010; Kurotani et al., 2014; Pejaver et al., 2014), and by alternative splicing (Romero et al., 2006; Buljan et al., 2012, 2013; Uversky, 2014b). [...]IDPs/IDPRs are often able to fold differently while interacting with different binding partners (Dyson and Wright, 2005; Oldfield et al., 2008; Hsu et al., 2013). Since IDPs/IDPRs play a number of crucial roles in numerous biological processes, it is not surprising that some of these proteins are related to the pathogenesis of human disease, and to neurodegenerative processes in particular. [...]dysregulation and misfolding of the otherwise tightly controlled IDPs/IDPRs can result in their dysfunction, ultimately leading to the development of life-threatening pathological conditions.

We present an idea of protein molecules that challenges the traditional view of proteins as simple molecular machines and suggests instead that they exhibit a basic form of “intelligence”. The idea stems from suggestions coming from Integrated Information Theory (IIT), network theory, and allostery to explore how proteins process information, adapt to their environment, and even show memory-like behaviors. We define protein intelligence using IIT and focus on how proteins integrate information (in terms of the parameter Φ coming from IIT) and balance their core (stable, ordered regions) and periphery (flexible, disordered regions). This balance allows proteins to remain stable while adapting to changes and operating in a critical state where order and disorder coexist. We summarize recent findings on conformational memory, allosteric regulation, protein intrinsic disorder, liquid-liquid phase separation, and critical transitions, and compare protein behavior to other complex systems like ecosystems and neural networks. While our perspective offers a unified framework to understand proteins, it also raises questions about applying intelligence concepts to molecular systems. We discuss how this understanding could advance protein engineering, drug design, and synthetic biology, while at the same time acknowledging the challenges of creating adaptive, “intelligent” proteins. This concept bridges the gap between mechanistic and systems-level views of proteins and offers a comprehensive understanding of their dynamic and adaptive nature. We have tried to redefine the traditionally metaphorical concept of “intelligence” in biochemistry as a measurable property while simultaneously establishing the material foundation of protein intelligence through the identification of fundamental elements such as memory and learning in molecular systems.

In addition to the “traditional” proteins characterized by the unique crystal-like structures needed for unique functions, it is increasingly recognized that many proteins or protein regions (collectively known as intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs)), being biologically active, do not have a specific 3D-structure in their unbound states under physiological conditions. There are also subtler categories of disorder, such as conditional (or dormant) disorder and partial disorder. Both the ability of a protein/region to fold into a well-ordered functional unit or to stay intrinsically disordered but functional are encoded in the amino acid sequence. Structurally, IDPs/IDPRs are characterized by high spatiotemporal heterogeneity and exist as dynamic structural ensembles. It is important to remember, however, that although structure and disorder are often treated as binary states, they actually sit on a structural continuum.

Cells are inhomogeneously crowded, possessing a wide range of intracellular liquid droplets abundantly present in the cytoplasm of eukaryotic and bacterial cells, in the mitochondrial matrix and nucleoplasm of eukaryotes, and in the chloroplast’s stroma of plant cells. These proteinaceous membrane-less organelles (PMLOs) not only represent a natural method of intracellular compartmentalization, which is crucial for successful execution of various biological functions, but also serve as important means for the processing of local information and rapid response to the fluctuations in environmental conditions. Since PMLOs, being complex macromolecular assemblages, possess many characteristic features of liquids, they represent highly dynamic (or fuzzy) protein–protein and/or protein–nucleic acid complexes. The biogenesis of PMLOs is controlled by specific intrinsically disordered proteins (IDPs) and hybrid proteins with ordered domains and intrinsically disordered protein regions (IDPRs), which, due to their highly dynamic structures and ability to facilitate multivalent interactions, serve as indispensable drivers of the biological liquid–liquid phase transitions (LLPTs) giving rise to PMLOs. In this article, the importance of the disorder-based supramolecular fuzziness for LLPTs and PMLO biogenesis is discussed.

Transitions between the unfolded and native states of the ordered globular proteins are accompanied by the accumulation of several intermediates, such as pre-molten globules, wet molten globules, and dry molten globules. Structurally equivalent conformations can serve as native functional states of intrinsically disordered proteins. This overview captures the characteristics and importance of these molten globules in both structured and intrinsically disordered proteins. It also discusses examples of engineered molten globules. The formation of these intermediates under conditions of macromolecular crowding and their interactions with nanomaterials are also reviewed.

Background Amyloid aggregate deposition is the key feature of Alzheimer’s disease. The proteinaceous aggregates found in the afflicted brain are the intra-neuronal neurofibrillary tangles formed by the microtubule-associated protein Tau and extracellular deposits, senile plaques, of amyloid beta (Aβ) peptide proteolytically derived from the amyloid precursor protein. Accumulation of these aggregates has manifestations in the later stages of the disease, such as memory loss and cognitive inabilities originating from the neuronal dysfunction, neurodegeneration, and brain atrophy. Treatment of this disease at the late stages is difficult, and many clinical trials have failed. Hence, the goal is to find means capable of preventing the aggregation of these intrinsically disordered proteins by inhibiting the early stages of their pathological transformations. Polyphenols are known to be neuroprotective agents with the noticeable potential against many neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Prion diseases. Methods We analyzed the capability of Baicalein to inhibit aggregation of human Tau protein by a multifactorial analysis that included several biophysical and biochemical techniques. Results The potency of Baicalein, a polyphenol from the Scutellaria baicalensis Georgi , against in vitro Tau aggregation and PHF dissolution has been screened and validated. ThS fluorescence assay revealed the potent inhibitory activity of Baicalein, whereas ANS revealed its mechanism of Tau inhibition viz. by oligomer capture and dissociation. In addition, Baicalein dissolved the preformed mature fibrils of Tau thereby possessing a dual target action. Tau oligomers formed by Baicalein were non-toxic to neuronal cells, highlighting its role as a potent molecule to be screened against AD. Conclusion In conclusion, Baicalein inhibits aggregation of hTau40 by enhancing the formation of SDS-stable oligomers and preventing fibril formation. Baicalein-induced oligomers do not affect the viability of the neuroblastoma cells. Therefore, Baicalein can be considered as a lead molecule against Tau pathology in AD. 7WG9tgRW_24b19dTX7j1bj Video Abstract

Obviously, the discussion of different factors that could have contributed to the origin of life and evolution is clear speculation, since there is no way of checking the validity of most of the related hypotheses in practice, as the corresponding events not only already happened, but took place in a very distant past. However, there are a few undisputable facts that are present at the moment, such as the existence of a wide variety of living forms and the abundant presence of intrinsically disordered proteins (IDPs) or hybrid proteins containing ordered domains and intrinsically disordered regions (IDRs) in all living forms. Since it seems that the currently existing living forms originated from a common ancestor, their variety is a result of evolution. Therefore, one could ask a logical question of what role(s) the structureless and highly dynamic but vastly abundant and multifunctional IDPs/IDRs might have in evolution. This study represents an attempt to consider various ideas pertaining to the potential roles of protein intrinsic disorder in the origin of life and evolution.

Contrarily to the general believe, many biologically active proteins lack stable tertiary and/or secondary structure under physiological conditions in vitro. These intrinsically disordered proteins (IDPs) are highly abundant in nature and many of them are associated with various human diseases. The functional repertoire of IDPs complements the functions of ordered proteins. Since IDPs constitute a significant portion of any given proteome, they can be combined in an unfoldome; which is a portion of the proteome including all IDPs (also known as natively unfolded proteins, therefore, unfoldome), and describing their functions, structures, interactions, evolution, and so forth. Amino acid sequence and compositions of IDPs are very different from those of ordered proteins, making possible reliable identification of IDPs at the proteome level by various computational means. Furthermore, IDPs possess a number of unique structural properties and are characterized by a peculiar conformational behavior, including their high stability against low pH and high temperature and their structural indifference toward the unfolding by strong denaturants. These peculiarities were shown to be useful for elaboration of the experimental techniques for the large-scale identification of IDPs in various organisms. Some of the computational and experimental tools for the unfoldome discovery are discussed in this review.