Intrinsically Disordered Proteins in Chronic Diseases

Kulkarni, Prakash; Uversky, Vladimir N.

doi:10.3390/biom9040147

Cited by 60 publications

(44 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This result is particularly interesting because misexpressed, misprocessed and dysregulated IDPs are highly prone to engage in promiscuous interactions with other proteins, DNA or RNA molecules, causing pathological states. [ 127 ] Moreover, an “evolutionary biochemistry” approach based on molecular modelling and NMR experiments suggests that interactions in a proteome start with low‐affinity IDPs that become structured and specific through progressive mutations. [ 128 ] Thus, the promiscuity of IDP and their ability to interact at all levels in protein‐protein, protein‐DNA and protein‐RNA layers could be the origin of the versatility of gene networks but also its weakness.…”

Section: Structural Disorder and Rna‐binding Ability Are Key Determinmentioning

confidence: 99%

RNA‐protein interactions: Central players in coordination of regulatory networks

et al. 2020

View full text Add to dashboard Cite

Changes in the abundance of protein and RNA molecules can impair the formation of complexes in the cell leading to toxicity and death. Here we exploit the information contained in protein, RNA and DNA interaction networks to provide a comprehensive view of the regulation layers controlling the concentration‐dependent formation of assemblies in the cell. We present the emerging concept that RNAs can act as scaffolds to promote the formation ribonucleoprotein complexes and coordinate the post‐transcriptional layer of gene regulation. We describe the structural and interaction network properties that characterize the ability of protein and RNA molecules to interact and phase separate in liquid‐like compartments. Finally, we show that presence of structurally disordered regions in proteins correlate with the propensity to undergo liquid‐to‐solid phase transitions and cause human diseases. Also see the video abstract here https://youtu.be/kfpqibsNfS0

show abstract

Section: Structural Disorder and Rna‐binding Ability Are Key Determinmentioning

confidence: 99%

RNA‐protein interactions: Central players in coordination of regulatory networks

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Generally, IDPs/IDRs are enriched in proteins involved in signaling and regulatory functions, including transcription regulation, cell cycle, mRNA processing, scaffolding, and apoptosis . Consequently, dysregulation of IDPs/IDRs are associated with a variety of human diseases . Most recently, many IDPs/IDRs are found to be able to undergo liquid–liquid phase separation (LLPS), which is related to the assembling of membraneless organelles in vivo .…”

Section: Introductionmentioning

confidence: 99%

“…6,14,15,[18][19][20][21][22][23][24][25][26][27][28][29][30][31] Consequently, dysregulation of IDPs/IDRs are associated with a variety of human diseases. [32][33][34][35][36][37][38][39][40][41][42][43][44] Most recently, many IDPs/IDRs are found to be able to undergo liquid-liquid phase separation (LLPS), which is related to the assembling of membraneless organelles in vivo. [45][46][47][48][49][50][51][52][53] So far, studies on IDPs/IDRs have greatly extended our understanding on the sequence-structurefunction relationship of proteins.…”

mentioning

confidence: 99%

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

et al. 2019

View full text Add to dashboard Cite

The sequence–structure–function paradigm of proteins has been revolutionized by the discovery of intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs). In contrast to traditional ordered proteins, IDPs/IDRs are unstructured under physiological conditions. The absence of well‐defined three‐dimensional structures in the free state of IDPs/IDRs is fundamental to their function. Folding upon binding is an important mode of molecular recognition for IDPs/IDRs. While great efforts have been devoted to investigating the complex structures and binding kinetics and affinities, our knowledge on the binding mechanisms of IDPs/IDRs remains very limited. Here, we review recent advances on the binding mechanisms of IDPs/IDRs. The structures and kinetic parameters of IDPs/IDRs can vary greatly, and the binding mechanisms can be highly dependent on the structural properties of IDPs/IDRs. IDPs/IDRs can employ various combinations of conformational selection and induced fit in a binding process, which can be templated by the target and/or encoded by the IDP/IDR. Further studies should provide deeper insights into the molecular recognition of IDPs/IDRs and enable the rational design of IDP/IDR binding mechanisms in the future.

show abstract

“…Most of the proteins associated with diseases, such as cancer, AD, PD, diabetes, and cardiovascular disease are either IDPs or contain long IDPRs, and misbehavior or mutations in the IDPs/IDPRs have broad involvement in the pathogenesis of these diseases [44][45][46][47][48][49]. From overall analysis, we found that most of the UPS proteins are intrinsically disordered and are closely linked with the pathophysiology of many diseases, such as cancer, AD, PD, ALS, HD, etc.…”

Section: Intrinsic Disorder In the Proteins Of Ubiquitin Proteasomal mentioning

confidence: 93%

“…Intrinsically disordered proteins (IDPs) and IDP regions (IDPRs) are the proteins or regions of proteins that lack well-defined, three-dimensional unique structures and show structural transition upon binding with their biological partners [44][45][46][47][48][49]. IDPs/IDPRs are commonly found in all organisms, being more abundant in eukaryote proteomes [50][51][52].…”

Section: Introductionmentioning

confidence: 99%

Unstructured Biology of Proteins from Ubiquitin-Proteasome System: Roles in Cancer and Neurodegenerative Diseases

et al. 2020

Self Cite

View full text Add to dashboard Cite

The 26S proteasome is a large (~2.5 MDa) protein complex consisting of at least 33 different subunits and many other components, which form the ubiquitin proteasomal system (UPS), an ATP-dependent protein degradation system in the cell. UPS serves as an essential component of the cellular protein surveillance machinery, and its dysfunction leads to cancer, neurodegenerative and immunological disorders. Importantly, the functions and regulations of proteins are governed by the combination of ordered regions, intrinsically disordered protein regions (IDPRs) and molecular recognition features (MoRFs). The structure–function relationships of UPS components have not been identified completely; therefore, in this study, we have carried out the functional intrinsic disorder and MoRF analysis for potential neurodegenerative disease and anti-cancer targets of this pathway. Our report represents the presence of significant intrinsic disorder and disorder-based binding regions in several UPS proteins, such as extraproteasomal polyubiquitin receptors (UBQLN1 and UBQLN2), proteasome-associated polyubiquitin receptors (ADRM1 and PSMD4), deubiquitinating enzymes (DUBs) (ATXN3 and USP14), and ubiquitinating enzymes (E2 (UBE2R2) and E3 (STUB1) enzyme). We believe this study will have implications for the conformation-specific roles of different regions of these proteins. This will lead to a better understanding of the molecular basis of UPS-associated diseases.

show abstract

Intrinsically Disordered Proteins in Chronic Diseases

Abstract: It is now increasingly evident that a large fraction of the human proteome comprises proteins that, under physiological conditions, lack fixed, ordered 3D structures as a whole or have segments that are not likely to form a defined 3D structure [...]

Cited by 60 publications

References 44 publications

RNA‐protein interactions: Central players in coordination of regulatory networks

RNA‐protein interactions: Central players in coordination of regulatory networks

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

Unstructured Biology of Proteins from Ubiquitin-Proteasome System: Roles in Cancer and Neurodegenerative Diseases

Contact Info

Product

Resources

About