•Eukaryotic cells are inhomogeneously crowded and contain various cellular bodies.•Some of these bodies are proteinaceous membrane-less organelles (PMLOs)•PMLOs are formed as a result of highly ...controlled liquid-liquid phase transitions.•The interior of these condensed liquid droplets represents an overcrowded milieu.•PMLOs are invariantly enriched in intrinsically disordered proteins.•Intrinsic disorder is crucial for formation, disassembly, and functionality of PMLOs.
Although the cellular interior is crowded with various biological macromolecules, the distribution of these macromolecules is highly inhomogeneous. Eukaryotic cells contain numerous proteinaceous membrane-less organelles (PMLOs), which are condensed liquid droplets formed as a result of the reversible and highly controlled liquid-liquid phase transitions. The interior of these cellular bodies represents an overcrowded milieu, since their protein concentrations are noticeably higher than those of the crowded cytoplasm and nucleoplasm. PMLOs are different in size, shape, and composition, and almost invariantly contain intrinsically disordered proteins (e.g., eIF4B and TDP43 in stress granules, TTP in P-bodies, RDE-12 in nuage, RNG105 in RNA granules, centrins in centrosomes, NOPP140 in nucleoli, SRSF4 in nuclear speckles, Saf-B in nuclear stress bodies, NOLC1 in Cajal bodies, CBP in PML nuclear bodies, SOX9 in paraspeckles, KSRP in perinucleolar compartment, and hnRNPG and Sam68 in Sam68 nuclear body, to name a few), which indicates that the formation of these phase-separated droplets is crucially dependent on intrinsic disorder. The goal of this review is to show the roles of intrinsic disorder in the magic behind biological liquid-liquid phase transitions that lead to the formation of PMLOs.
The abundant existence of proteins and regions that possess specific functions without being uniquely folded into unique 3D structures has become accepted by a significant number of protein ...scientists. Sequences of these intrinsically disordered proteins (IDPs) and IDP regions (IDPRs) are characterized by a number of specific features, such as low overall hydrophobicity and high net charge which makes these proteins predictable. IDPs/IDPRs possess large hydrodynamic volumes, low contents of ordered secondary structure, and are characterized by high structural heterogeneity. They are very flexible, but some may undergo disorder to order transitions in the presence of natural ligands. The degree of these structural rearrangements varies over a very wide range. IDPs/IDPRs are tightly controlled under the normal conditions and have numerous specific functions that complement functions of ordered proteins and domains. When lacking proper control, they have multiple roles in pathogenesis of various human diseases. Gaining structural and functional information about these proteins is a challenge, since they do not typically “freeze” while their “pictures are taken.” However, despite or perhaps because of the experimental challenges, these fuzzy objects with fuzzy structures and fuzzy functions are among the most interesting targets for modern protein research. This review briefly summarizes some of the recent advances in this exciting field and considers some of the basic lessons learned from the analysis of physics, chemistry, and biology of IDPs.
PDB Code(s): 3PHY, 2KX6
Research of a past decade and a half leaves no doubt that complete understanding of protein functionality requires close consideration of the fact that many functional proteins do not have ...well-folded structures. These intrinsically disordered proteins (IDPs) and proteins with intrinsically disordered protein regions (IDPRs) are highly abundant in nature and play a number of crucial roles in a living cell. Their functions, which are typically associated with a wide range of intermolecular interactions where IDPs possess remarkable binding promiscuity, complement functional repertoire of ordered proteins. All this requires a close attention to the peculiarities of biophysics of these proteins. In this review, some key biophysical features of IDPs are covered. In addition to the peculiar sequence characteristics of IDPs these biophysical features include sequential, structural, and spatiotemporal heterogeneity of IDPs; their rough and relatively flat energy landscapes; their ability to undergo both induced folding and induced unfolding; the ability to interact specifically with structurally unrelated partners; the ability to gain different structures at binding to different partners; and the ability to keep essential amount of disorder even in the bound form. IDPs are also characterized by the “turned-out” response to the changes in their environment, where they gain some structure under conditions resulting in denaturation or even unfolding of ordered proteins. It is proposed that the heterogeneous spatiotemporal structure of IDPs/IDPRs can be described as a set of foldons, inducible foldons, semi-foldons, non-foldons, and unfoldons. They may lose their function when folded, and activation of some IDPs is associated with the awaking of the dormant disorder. It is possible that IDPs represent the “edge of chaos” systems which operate in a region between order and complete randomness or chaos, where the complexity is maximal. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.
► Intrinsically disordered proteins (IDPs) are important members of the protein kingdom. ► They possess remarkable sequential, structural, spatiotemporal, and functional heterogeneity. ► They have rough and relatively flat energy landscapes. ► They might contain foldons, inducible foldons, semi-foldons and non-foldons. ► IDPs can be considered as the “edge of chaos” systems.
Although it is one of the most studied proteins, p53 continues to be an enigma. This protein has numerous biological functions, possesses intrinsically disordered regions crucial for its ...functionality, can form both homo-tetramers and isoform-based hetero-tetramers, and is able to interact with many binding partners. It contains numerous posttranslational modifications, has several isoforms generated by alternative splicing, alternative promoter usage or alternative initiation of translation, and is commonly mutated in different cancers. Therefore, p53 serves as an important illustration of the protein structure-function continuum concept, where the generation of multiple proteoforms by various mechanisms defines the ability of this protein to have a multitude of structurally and functionally different states. Considering p53 in the light of a proteoform-based structure-function continuum represents a non-canonical and conceptually new contemplation of structure, regulation, and functionality of this important protein.
Biologically active but floppy proteins represent a new reality of modern protein science. These intrinsically disordered proteins (IDPs) and hybrid proteins containing ordered and intrinsically ...disordered protein regions (IDPRs) constitute a noticeable part of any given proteome. Functionally, they complement ordered proteins, and their conformational flexibility and structural plasticity allow them to perform impossible tricks and be engaged in biological activities that are inaccessible to well folded proteins with their unique structures. The major goals of this minireview are to show that, despite their simplified amino acid sequences, IDPs/IDPRs are complex entities often resembling chaotic systems, are structurally and functionally heterogeneous, and can be considered an important part of the structure-function continuum. Furthermore, IDPs/IDPRs are everywhere, and are ubiquitously engaged in various interactions characterized by a wide spectrum of binding scenarios and an even wider spectrum of structural and functional outputs.
Proteins are structurally heterogeneous and comprise folded regions with variable conformational stabilities and intrinsically disordered protein regions that do not have well‐folded structures. Even ...small, well‐folded single‐domain proteins are structurally heterogeneous and contain multiple foldon units with different conformational stability. Although the ability of many intrinsically disordered protein regions to undergo at least partial folding at interaction with specific binding partners is a well‐established fact, recent studies have revealed that functions of some ordered proteins rely on the decrease in the amount of their ordered structure and require local or even global functional unfolding. This functional unfolding is induced by transient alterations in protein environment or by modification of protein structure and can be reversed as soon as the environment is restored or the modification is removed. Therefore, the important features of these conditionally disordered protein regions (or unfoldons) are the induced nature and the transient character of their disorder. In other words, structurally any protein can be described as a modular assembly of foldons, inducible foldons, semi‐foldons, nonfoldons and unfoldons. Obviously, differently ordered/disordered proteins and protein regions can possess very different functional repertoires. This review represents some of the key functions of transiently and intrinsically disordered protein regions.
The ideas that proteins might possess specific functions without being uniquely folded into rigid 3D-structures and that these floppy polypeptides might constitute a noticeable part of any given ...proteome would have been considered as a preposterous fiction 15 or even 10 years ago. The situation has changed recently, and the existence of functional yet intrinsically disordered proteins and regions has become accepted by a significant number of protein scientists. These fuzzy objects with fuzzy structures and fuzzy functions are among the most interesting and attractive targets for modern protein research. This review summarizes some of the major discoveries and breakthroughs in the field of intrinsic disorder by representing related concepts and definitions.
It is clear now that eukaryotic cells contain numerous membrane-less organelles, many of which are formed in response to changes in the cellular environment. Being typically liquid in nature, many of ...these organelles can be described as products of the reversible and highly controlled liquid–liquid phase transitions in biological systems. Many of these membrane-less organelles are complex coacervates containing (almost invariantly) intrinsically disordered proteins and often nucleic acids. It seems that the lack of stable structure in major proteinaceous constituents of these organelles is crucial for the formation of phase-separated droplets. This review considers several biologically relevant liquid–liquid phase transitions, introduces some general features attributed to intrinsically disordered proteins, represents several illustrative examples of intrinsic disorder-based phase separation, and provides some reasons for the abundance of intrinsically disordered proteins in organelles formed as a result of biological liquid–liquid phase transitions.
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•Eukaryotic cells contain numerous membrane-less organelles with different compositions.•These organelles are formed in response to changes in the cellular environment.•They are products of the reversible and highly controlled liquid–liquid phase transitions.•Major proteinaceous constituents of these organelles are intrinsically disordered proteins.•Lack of stable structure in these proteins is crucial for the formation of phase-separated droplets.
Recognition of the natural abundance and functional importance of intrinsically disordered proteins (IDPs), and protein hybrids that contain both intrinsically disordered protein regions (IDPRs) and ...ordered regions, is changing protein science. IDPs and IDPRs, i.e., functional proteins and protein regions without unique structures, can often be found in all organisms, and typically play vital roles in various biological processes. Disorder-based functionality complements the functions of ordered proteins and domains. However, by virtue of their existence, IDPs/IDPRs, which are characterized by remarkable conformational flexibility and structural plasticity, break multiple rules established over the years to explain structure, folding, and functionality of well-folded proteins with unique structures. Despite the general belief that unique biological functions of proteins require unique 3D-structures (which dominated protein science for more than a century), structure-less IDPs/IDPRs are functional, being able to engage in biological activities and perform impossible tricks that are highly unlikely for ordered proteins. With their exceptional spatio-temporal heterogeneity and high conformational flexibility, IDPs/IDPRs represent complex systems that act at the edge of chaos and are specifically tunable by various means. In this article, some of the wonders of intrinsic disorder are discussed as illustrations of their “mysterious” (meta)physics.
It is clear now that proteins lacking ordered structure, generally known as intrinsically disordered proteins (IDPs), possess numerous biological functions that complement functional repertoires of ...ordered proteins. IDPs are common in nature, and abundantly found to be involved in the pathogenesis of various diseases. These proteins participate in various biological processes and play crucial roles in regulation of functions of their binding partners. Often, disorder-to-order transition induced by the IDP binding to a specific partner defines the low-affinity - high-specificity signaling interactions. Although many IDPs undergo a disorder-to-order transition upon binding, large fraction of IDPs can preserve significant amount of disorder even in their bound states. IDPs can participate in one-tomany and many-to-one interactions, where one intrinsically disordered protein region (IDPR) binds to multiple partners potentially gaining very different structures in the bound state, or where multiple unrelated IDPs/IDPRs bind to one partner. Binding functions of IDPs and IDPRs are controlled by various means, such as numerous posttranslational modifications and alternative splicing. Some of the aspects of the intrinsic disorder-based protein interactions and modes of their regulation are considered in this review.
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