Predicting condensate formation of protein and RNA under various environmental conditions.

BACKGROUND: Liquid-liquid phase separation (LLPS) by biomolecules plays a central role in various biological phenomena and has garnered significant attention. The behavior of LLPS is strongly influenced by the characteristics of RNAs and environmental factors such as pH and temperature, as well as the properties of proteins. Recently, several databases recording LLPS-related biomolecules have been established, and prediction models of LLPS-related phenomena have been explored using these databases. However, a prediction model that concurrently considers proteins, RNAs, and experimental conditions has not been developed due to the limited information available from individual experiments in public databases. RESULTS: To address this challenge, we have constructed a new dataset, RNAPSEC, which serves each experiment as a data point. This dataset was accomplished by manually collecting data from public literature. Utilizing RNAPSEC, we developed two prediction models that consider a protein, RNA, and experimental conditions. The first model can predict the LLPS behavior of a protein and RNA under given experimental conditions. The second model can predict the required conditions for a given protein and RNA to undergo LLPS. CONCLUSIONS: RNAPSEC and these prediction models are expected to accelerate our understanding of the roles of proteins, RNAs, and environmental factors in LLPS.

HYPK: A marginally disordered protein sensitive to charge decoration.

Intrinsically disordered proteins (IDPs) that lie close to the empirical boundary separating IDPs and folded proteins in Uversky's charge-hydropathy plot may behave as "marginal IDPs" and sensitively switch conformation upon changes in environment (temperature, crowding, and charge screening), sequence, or both. In our search for such a marginal IDP, we selected Huntingtin-interacting protein K (HYPK) near that boundary as a candidate; PKIα, also near that boundary, has lower secondary structure propensity; and Crk1, just across the boundary on the folded side, has higher secondary structure propensity. We used a qualitative Förster resonance energy transfer-based assay together with circular dichroism to simultaneously probe global and local conformation. HYPK shows several unique features indicating marginality: a cooperative transition in end-to-end distance with temperature, like Crk1 and folded proteins, but unlike PKIα; enhanced secondary structure upon crowding, in contrast to Crk1 and PKIα; and a cross-over from salt-induced expansion to compaction at high temperature, likely due to a structure-to-disorder transition not seen in Crk1 and PKIα. We then tested HYPK's sensitivity to charge patterning by designing charge-flipped variants including two specific sequences with identical amino acid composition that markedly differ in their predicted size and response to salt. The experimentally observed trends, also including mutants of PKIα, verify the predictions from sequence charge decoration metrics. Marginal proteins like HYPK show features of both folded and disordered proteins that make them sensitive to physicochemical perturbations and structural control by charge patterning.

Functional in vitro diversity of an intrinsically disordered plant protein during freeze-thawing is encoded by its structural plasticity.

Intrinsically disordered late embryogenesis abundant (LEA) proteins play a central role in the tolerance of plants and other organisms to dehydration brought upon, for example, by freezing temperatures, high salt concentration, drought or desiccation, and many LEA proteins have been found to stabilize dehydration-sensitive cellular structures. Their conformational ensembles are highly sensitive to the environment, allowing them to undergo conformational changes and adopt ordered secondary and quaternary structures and to participate in formation of membraneless organelles. In an interdisciplinary approach, we discovered how the functional diversity of the Arabidopsis thaliana LEA protein COR15A found in vitro is encoded in its structural repertoire, with the stabilization of membranes being achieved at the level of secondary structure and the stabilization of enzymes accomplished by the formation of oligomeric complexes. We provide molecular details on intra- and inter-monomeric helix-helix interactions, demonstrate how oligomerization is driven by an α-helical molecular recognition feature (α-MoRF) and provide a rationale that the formation of noncanonical, loosely packed, right-handed coiled-coils might be a recurring theme for homo- and hetero-oligomerization of LEA proteins.

Best practices for the manual curation of intrinsically disordered proteins in DisProt.

The DisProt database is a resource containing manually curated data on experimentally validated intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) from the literature. Developed in 2005, its primary goal was to collect structural and functional information into proteins that lack a fixed three-dimensional structure. Today, DisProt has evolved into a major repository that not only collects experimental data but also contributes to our understanding of the IDPs/IDRs roles in various biological processes, such as autophagy or the life cycle mechanisms in viruses or their involvement in diseases (such as cancer and neurodevelopmental disorders). DisProt offers detailed information on the structural states of IDPs/IDRs, including state transitions, interactions and their functions, all provided as curated annotations. One of the central activities of DisProt is the meticulous curation of experimental data from the literature. For this reason, to ensure that every expert and volunteer curator possesses the requisite knowledge for data evaluation, collection and integration, training courses and curation materials are available. However, biocuration guidelines concur on the importance of developing robust guidelines that not only provide critical information about data consistency but also ensure data acquisition.This guideline aims to provide both biocurators and external users with best practices for manually curating IDPs and IDRs in DisProt. It describes every step of the literature curation process and provides use cases of IDP curation within DisProt. Database URL: https://disprot.org/.

Assessment of Disordered Linker Predictions in the CAID2 Experiment.

Disordered linkers (DLs) are intrinsically disordered regions that facilitate movement between adjacent functional regions/domains, contributing to many key cellular functions. The recently completed second Critical Assessments of protein Intrinsic Disorder prediction (CAID2) experiment evaluated DL predictions by considering a rather narrow scenario when predicting 40 proteins that are already known to have DLs. We expand this evaluation by using a much larger set of nearly 350 test proteins from CAID2 and by investigating three distinct scenarios: (1) prediction residues in DLs vs. in non-DL regions (typical use of DL predictors); (2) prediction of residues in DLs vs. other disordered residues (to evaluate whether predictors can differentiate residues in DLs from other types of intrinsically disordered residues); and (3) prediction of proteins harboring DLs. We find that several methods provide relatively accurate predictions of DLs in the first scenario. However, only one method, APOD, accurately identifies DLs among other types of disordered residues (scenario 2) and predicts proteins harboring DLs (scenario 3). We also find that APOD's predictive performance is modest, motivating further research into the development of new and more accurate DL predictors. We note that these efforts will benefit from a growing amount of training data and the availability of sophisticated deep network models and emphasize that future methods should provide accurate results across the three scenarios.

Multiscale Computational Framework for the Liquid-Liquid Phase Separation of Intrinsically Disordered Proteins.

The reversible assembly of intrinsically disordered proteins (IDPs) to form membraneless organelles (MLOs) is a fundamental process involved in the spatiotemporal regulation in living cells. MLOs formed via liquid-liquid phase separation (LLPS) serve as molecule-enhancing hubs to regulate cell functions. Owing to the complexity and dynamic nature of the protein assembly via a network of weak inter- and intra-molecular interactions, it is challenging to describe and predict the LLPS behavior. We have developed a multiscale computational model for IDPs, using the fused in sarcoma (FUS) protein and its variants as illustrative examples. To simplify the description of protein, FUS is represented as a linear chain of stickers interspaced by spacers, as inspired by the associative polymer theory. Low-complexity aromatic-rich kinked segments (LARKS) available in FUS were identified using LARKSdb and represented as "stickers". The pairwise potential energies of each pair of stickers and their ß-sheet-forming propensity were estimated via molecular docking and all atomistic molecular dynamics (AA-MD) simulations. Subsequently, FUS chains were randomly positioned in a cubic lattice as coarse-grained (CG) beads, with the bead assignment based on the Kuhn length estimation of stickers and spacers. Stochastic FUS movements were modeled by Monte Carlo (MC) simulations. In addition to the Metropolis algorithm, discretized pair potential distributions between stickers were considered in the move acceptance criteria. The chosen pair potential represents one of the possible binding energy states, with its probability determined by the frequency of the binding energy distribution histogram. The fluctuations of averaged radial distribution functions (RDFs) in successive MC trial move intervals of equilibrated lattice MC simulations were used to indicate the dynamic nature of assembly/disassembly of the protein chains. This multiscale computational framework provides an economical and efficient way of predicting and describing the LLPS behavior of IDPs.

Macromolecular condensation organizes nucleolar sub-phases to set up a pH gradient.

Nucleoli are multicomponent condensates defined by coexisting sub-phases. We identified distinct intrinsically disordered regions (IDRs), including acidic (D/E) tracts and K-blocks interspersed by E-rich regions, as defining features of nucleolar proteins. We show that the localization preferences of nucleolar proteins are determined by their IDRs and the types of RNA or DNA binding domains they encompass. In vitro reconstitutions and studies in cells showed how condensation, which combines binding and complex coacervation of nucleolar components, contributes to nucleolar organization. D/E tracts of nucleolar proteins contribute to lowering the pH of co-condensates formed with nucleolar RNAs in vitro. In cells, this sets up a pH gradient between nucleoli and the nucleoplasm. By contrast, juxta-nucleolar bodies, which have different macromolecular compositions, featuring protein IDRs with very different charge profiles, have pH values that are equivalent to or higher than the nucleoplasm. Our findings show that distinct compositional specificities generate distinct physicochemical properties for condensates.

A set of cross-correlated relaxation experiments to probe the correlation time of two different and complementary spin pairs.

Intrinsically disordered proteins (IDPs) defy the conventional structure-function paradigm by lacking a well-defined tertiary structure and exhibiting inherent flexibility. This flexibility leads to distinctive spin relaxation modes, reflecting isolated and specific motions within individual peptide planes. In this work, we propose a new pulse sequence to measure the longitudinal 13C' CSA-13C'-13Cα DD CCR rate [Formula: see text] and present a novel 3D version of the transverse [Formula: see text] CCR rate, adopting the symmetrical reconversion approach. We combined these rates with the analogous ΓxyN/NH and ΓzN/NH CCR rates to derive residue-specific correlation times for both spin-pairs within the same peptide plane. The presented approach offers a straightforward and intuitive way to compare the correlation times of two different and complementary spin vectors, anticipated to be a valuable aid to determine IDPs backbone dihedral angles distributions. We performed the proposed experiments on two systems: a folded protein ubiquitin and Coturnix japonica osteopontin, a prototypical IDP. Comparative analyses of the results show that the correlation times of different residues vary more for IDPs than globular proteins, indicating that the dynamics of IDPs is largely heterogeneous and dominated by local fluctuations.

Cyclophilin A supports translation of intrinsically disordered proteins and affects haematopoietic stem cell ageing.

Loss of protein function is a driving force of ageing. We have identified peptidyl-prolyl isomerase A (PPIA or cyclophilin A) as a dominant chaperone in haematopoietic stem and progenitor cells. Depletion of PPIA accelerates stem cell ageing. We found that proteins with intrinsically disordered regions (IDRs) are frequent PPIA substrates. IDRs facilitate interactions with other proteins or nucleic acids and can trigger liquid-liquid phase separation. Over 20% of PPIA substrates are involved in the formation of supramolecular membrane-less organelles. PPIA affects regulators of stress granules (PABPC1), P-bodies (DDX6) and nucleoli (NPM1) to promote phase separation and increase cellular stress resistance. Haematopoietic stem cell ageing is associated with a post-transcriptional decrease in PPIA expression and reduced translation of IDR-rich proteins. Here we link the chaperone PPIA to the synthesis of intrinsically disordered proteins, which indicates that impaired protein interaction networks and macromolecular condensation may be potential determinants of haematopoietic stem cell ageing.

Rheostats, toggles, and neutrals, Oh my! A new framework for understanding how amino acid changes modulate protein function.

Advances in personalized medicine and protein engineering require accurately predicting outcomes of amino acid substitutions. Many algorithms correctly predict that evolutionarily-conserved positions show "toggle" substitution phenotypes, which is defined when a few substitutions at that position retain function. In contrast, predictions often fail for substitutions at the less-studied "rheostat" positions, which are defined when different amino acid substitutions at a position sample at least half of the possible functional range. This review describes efforts to understand the impact and significance of rheostat positions: (1) They have been observed in globular soluble, integral membrane, and intrinsically disordered proteins; within single proteins, their prevalence can be up to 40%. (2) Substitutions at rheostat positions can have biological consequences and ∼10% of substitutions gain function. (3) Although both rheostat and "neutral" (defined when all substitutions exhibit wild-type function) positions are nonconserved, the two classes have different evolutionary signatures. (4) Some rheostat positions have pleiotropic effects on function, simultaneously modulating multiple parameters (e.g., altering both affinity and allosteric coupling). (5) In structural studies, substitutions at rheostat positions appear to cause only local perturbations; the overall conformations appear unchanged. (6) Measured functional changes show promising correlations with predicted changes in protein dynamics; the emergent properties of predicted, dynamically coupled amino acid networks might explain some of the complex functional outcomes observed when substituting rheostat positions. Overall, rheostat positions provide unique opportunities for using single substitutions to tune protein function. Future studies of these positions will yield important insights into the protein sequence/function relationship.

Mesophiles vs. Thermophiles: Untangling the Hot Mess of Intrinsically Disordered Proteins and Growth Temperature of Bacteria.

The dynamic structures and varying functions of intrinsically disordered proteins (IDPs) have made them fascinating subjects in molecular biology. Investigating IDP abundance in different bacterial species is crucial for understanding adaptive strategies in diverse environments. Notably, thermophilic bacteria have lower IDP abundance than mesophiles, and a negative correlation with optimal growth temperature (OGT) has been observed. However, the factors driving these trends are yet to be fully understood. We examined the types of IDPs present in both mesophiles and thermophiles alongside those unique to just mesophiles. The shared group of IDPs exhibits similar disorder levels in the two groups of species, suggesting that certain IDPs unique to mesophiles may contribute to the observed decrease in IDP abundance as OGT increases. Subsequently, we used quasi-independent contrasts to explore the relationship between OGT and IDP abundance evolution. Interestingly, we found no significant relationship between OGT and IDP abundance contrasts, suggesting that the evolution of lower IDP abundance in thermophiles may not be solely linked to OGT. This study provides a foundation for future research into the intricate relationship between IDP evolution and environmental adaptation. Our findings support further research on the adaptive significance of intrinsic disorder in bacterial species.

Backbone interactions and secondary structures in phase separation of disordered proteins.

Intrinsically disordered proteins (IDPs) are one of the major drivers behind the formation and characteristics of biomolecular condensates. Due to their inherent flexibility, the backbones of IDPs are significantly exposed, rendering them highly influential and susceptible to biomolecular phase separation. In densely packed condensates, exposed backbones have a heightened capacity to interact with neighboring protein chains, which might lead to strong coupling between the secondary structures and phase separation and further modulate the subsequent transitions of the condensates, such as aging and fibrillization. In this mini-review, we provide an overview of backbone-mediated interactions and secondary structures within biomolecular condensates to underscore the importance of protein backbones in phase separation. We further focus on recent advances in experimental techniques and molecular dynamics simulation methods for probing and exploring the roles of backbone interactions and secondary structures in biomolecular phase separation involving IDPs.

The Proteomic Analysis of Cancer-Related Alterations in the Human Unfoldome.

Many proteins lack stable 3D structures. These intrinsically disordered proteins (IDPs) or hybrid proteins containing ordered domains with intrinsically disordered protein regions (IDPRs) often carry out regulatory functions related to molecular recognition and signal transduction. IDPs/IDPRs constitute a substantial portion of the human proteome and are termed "the unfoldome". Herein, we probe the human breast cancer unfoldome and investigate relations between IDPs and key disease genes and pathways. We utilized bottom-up proteomics, MudPIT (Multidimensional Protein Identification Technology), to profile differentially expressed IDPs in human normal (MCF-10A) and breast cancer (BT-549) cell lines. Overall, we identified 2271 protein groups in the unfoldome of normal and cancer proteomes, with 148 IDPs found to be significantly differentially expressed in cancer cells. Further analysis produced annotations of 140 IDPs, which were then classified to GO (Gene Ontology) categories and pathways. In total, 65% (91 of 140) IDPs were related to various diseases, and 20% (28 of 140) mapped to cancer terms. A substantial portion of the differentially expressed IDPs contained disordered regions, confirmed by in silico characterization. Overall, our analyses suggest high levels of interactivity in the human cancer unfoldome and a prevalence of moderately and highly disordered proteins in the network.

Charge-Patterned Disordered Peptides Tune Intracellular Phase Separation in Bacteria.

Subcellular phase-separated compartments, known as biomolecular condensates, play an important role in the spatiotemporal organization of cells. To understand the sequence-determinants of phase separation in bacteria, we engineered protein-based condensates in Escherichia coli using electrostatic interactions as the main driving force. Minimal cationic disordered peptides were used to supercharge negative, neutral, and positive globular model proteins, enabling their phase separation with anionic biomacromolecules in the cell. The phase behavior was governed by the interaction strength between the cationic proteins and anionic biopolymers, in addition to the protein concentration. The interaction strength primarily depended on the overall net charge of the protein, but the distribution of charge between the globular and disordered domains also had an impact. Notably, the protein charge distribution between domains could tune mesoscale attributes such as the size, number, and subcellular localization of condensates within E. coli cells. The length and charge density of the disordered peptides had significant effects on protein expression levels, ultimately influencing the formation of condensates. Taken together, charge-patterned disordered peptides provide a platform for understanding the molecular grammar underlying phase separation in bacteria.

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The cellular response to mechanical stimuli depends largely on the structure of the cell itself and the abundance of intracellular cytomechanical proteins also plays a key role in the response to the stimulation of external mechanical signals. Liquid-liquid phase separation (LLPS) is the process by which proteins or protein-RNA complexes spontaneously separate and form two distinct "phases", ie, a low-concentration phase coexisting with a high-concentration phase. According to published findings, membrane-free organelles form and maintain their structures and regulate their internal biochemical activities through LLPS. LLPS, a novel mechanism for intracellular regulation of the biochemical reactions of biomacromolecules, plays a crucial role in modulating the responses of cytomechanical proteins. LLPS leads to the formation of highly concentrated liquid-phase condensates through multivalent interactions between biomacromolecules, thereby regulating a series of intracellular life activities. It has been reported that a variety of cytomechanical proteins respond to external mechanical signals through LLPS, which in turn affects biological behaviors such as cell growth, proliferation, spreading, migration, and apoptosis. Herein, we introduced the mechanisms of cytomechanics and LLPS. In addition, we presented the latest findings on cytomechanical protein phase separation, covering such issues as the regulation of focal adhesion maturation and mechanical signal transduction by LIM domain-containing protein 1 (LIMD1) phase separation, the regulation of intercellular tight junctions by zonula occludens (ZO) phase separation, and the regulation of cell proliferation and apoptosis by cytomechanical protein phase separation of the Hippo signaling pathway. The proposition of LLPS provides an explanation for the formation mechanism of intracellular membraneless organelles and supplies new approaches to understanding the biological functions of intracellular physiology or pathology. However, the molecular mechanisms by which LLPS drives focal adhesions and cell-edge dynamics are still not fully understood. It is not clear whether LLPS under in vitro conditions can occur under physiological conditions of organisms. There are still difficulties to be overcome in using LLPS to explain the interactions of multiple intracellular molecules. Researchers should pursue answers to these questions in the future.

Sequence Sensitivity in Membrane Remodeling by Polyampholyte Condensates.

Intrinsically disordered peptides (IDPs) have been found to undergo liquid-liquid phase separation (LLPS) and produce complex coacervates that play numerous regulatory roles in the cell. Recent experimental studies have discovered that LLPS at or near the membrane surface helps in the biomolecular organization during signaling events and can significantly alter the membrane morphology. However, the molecular mechanism and microscopic details of such processes still remain unclear. Here we study the effect of polyampholyte and polyelectrolyte condensation on two different anionic membranes, as they represent a majority of naturally occurring IDPs. The polyampholytes are fifty-residue polymers, made of glutamate(E) and lysine(K) with different charge patterns. The polyelectrolytes are separate chains of E25 and K25. We first calibrate the MARTINI v3.0 force field and then perform long-time-scale coarse-grained molecular dynamics simulations. We find that condensates formed by all the polyampholytes get adsorbed on the membrane. However, the strong polyampholytes (i.e., blocky sequences) can remodel the membranes more prominently than the weaker ones (i.e., scrambled sequences). Condensates formed by the blocky sequences induce a significant negative curvature (∼0.1 nm-1) and local demixing of lipids, whereas those by the scrambled sequences tend to wet the membrane to a greater extent without generating significant curvature or demixing. We perform several microscopic analyses to characterize the nature of the interaction between membranes and these condensates. Our analyses of interaction energetics reveal that membrane remodeling and/or wetting are favored by enhanced interactions between polyampholytes with lipids and the counterions.

A sequence-based model for identifying proteins undergoing liquid-liquid phase separation/forming fibril aggregates via machine learning.

Liquid-liquid phase separation (LLPS) and the solid aggregate (also referred to as amyloid aggregates) formation of proteins, have gained significant attention in recent years due to their associations with various physiological and pathological processes in living organisms. The systematic investigation of the differences and connections between proteins undergoing LLPS and those forming amyloid fibrils at the sequence level has not yet been explored. In this research, we aim to address this gap by comparing the two types of proteins across 36 features using collected data available currently. The statistical comparison results indicate that, 24 of the selected 36 features exhibit significant difference between the two protein groups. A LLPS-Fibrils binary classification model built on these 24 features using random forest reveals that the fraction of intrinsically disordered residues (FIDR ) is identified as the most crucial feature. While, in the further three-class LLPS-Fibrils-Background classification model built on the same screened features, the composition of cysteine and that of leucine show more significant contributions than others. Through feature ablation analysis, we finally constructed a model FLFB (Feature-based LLPS-Fibrils-Background protein predictor) using six refined features, with an average area under the receiver operating characteristics of 0.83. This work indicates using sequence features and a machine learning model, proteins undergoing LLPS or forming amyloid fibrils can be identified.

The effects of biological crowders on fibrillization, structure, diffusion, and conformational dynamics of α-synuclein.

α-synuclein is an intrinsically disordered protein (IDP) whose aggregation in presynaptic neuronal cells is a pathological hallmark of Lewy body formation and Parkinson's disease. This aggregation process is likely affected by the crowded macromolecular cellular environment. In this study, α-synuclein was studied in the presence of both a synthetic crowder, Ficoll70, and a biological crowder composed of lysed cells that better mimics the biocomplexity of the cellular environment. 15 N-1 H HSQC NMR results show similar α-synuclein chemical shifts in non-crowded and all crowded conditions implying that it remains similarly unstructured in all conditions. Nevertheless, both HSQC NMR and fluorescence measurements indicate that, only in the cell lysate, α-synuclein forms aggregates over a timescale of 48 h. 15 N-edited diffusion measurements indicate that all crowders slow down the α-synuclein's diffusivity. Interestingly, at high concentrations, α-synuclein diffuses faster in cell lysate than in Ficoll70, possibly due to additional soft (e.g., electrostatic or hydrophobic) interactions. 15 N-edited relaxation measurements show that some residues are more mobile in cell lysate than in Ficoll70; the rates that are most different are predominantly in hydrophobic residues. We thus examined cell lysates with reduced hydrophobicity and found slower dynamics (higher relaxation rates) in several α-synuclein residues. Taken together, these experiments suggest that while cell lysate does not substantially affect α-synuclein structure (HSQC spectra), it does affect chain dynamics and translational diffusion, and strongly affects aggregation over a timescale of days, in a manner that is different from either no crowder or an artificial crowder: soft hydrophobic interactions are implicated.

Protective roles of highly conserved motif 1 in tardigrade cytosolic-abundant heat soluble protein in extreme environments.

Tardigrades are remarkable microscopic animals that survive harsh conditions such as desiccation and extreme temperatures. Tardigrade-specific intrinsically disordered proteins (TDPs) play an essential role in the survival of tardigrades in extreme environments. Cytosolic-abundant heat soluble (CAHS) protein, a key TDP, is known to increase desiccation tolerance and to protect the activity of several enzymes under dehydrated conditions. However, the function and properties of each CAHS domain have not yet been elucidated in detail. Here, we aimed to elucidate the protective role of highly conserved motif 1 of CAHS in extreme environmental conditions. To examine CAHS domains, three protein constructs, CAHS Full (1-229), CAHS ∆Core (1-120_184-229), and CAHS Core (121-183), were engineered. The highly conserved CAHS motif 1 (124-142) in the CAHS Core formed an amphiphilic α helix, reducing the aggregate formation and protecting lactate dehydrogenase activity during dehydration-rehydration and freeze-thaw treatments, indicating that CAHS motif 1 in the CAHS Core was essential for maintaining protein solubility and stability. Aggregation assays and confocal microscopy revealed that the intrinsically disordered N- and C-terminal domains were more prone to aggregation under our experimental conditions. By explicating the functions of each domain in CAHS, our study proposes the possibility of using engineered proteins or peptides derived from CAHS as a potential candidate for biological applications in extreme environmental stress responses.

Proteasome activation: A novel strategy for targeting undruggable intrinsically disordered proteins.

Intrinsically disordered proteins (IDPs) are characterized by their inability to adopt well-defined tertiary structures under physiological conditions. Nonetheless, they often play pivotal roles in the progression of various diseases, including cancer, neurodegenerative disorders, and cardiovascular ailments. Owing to their inherent dynamism, conventional drug design approaches based on structural considerations encounter substantial challenges when applied to IDPs. Consequently, the pursuit of therapeutic interventions directed towards IDPs presents a complex endeavor. While there are indeed existing methodologies for targeting IDPs, they are encumbered by noteworthy constrains. Hence, there exists an imminent imperative to investigate more efficacious and universally applicable strategies for modulating IDPs. Here, we present an overview of the latest advancements in the research pertaining to IDPs, along with the indirect regulation approach involving the modulation of IDP degradation through proteasome. By comprehending these advancements in research, novel insights can be generated to facilitate the development of new drugs targeted at addressing the accumulation of IDPs in diverse pathological conditions.