scholarly journals Intrinsically Disordered Proteins as Regulators of Transient Biological Processes and as Untapped Drug Targets

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2118
Author(s):  
Yusuke Hosoya ◽  
Junko Ohkanda
Keyword(s):  
Drug Targets ◽  
Intrinsically Disordered Proteins ◽  
Dynamic Control ◽  
Disordered Proteins ◽  
Biological Processes ◽  
Phase Separations ◽  
Cellular Processes ◽  
Intrinsically Disordered ◽  
New Drug ◽  
Liquid Phase Separations

Intrinsically disordered proteins (IDPs) are critical players in the dynamic control of diverse cellular processes, and provide potential new drug targets because their dysregulation is closely related to many diseases. This review focuses on several medicinal studies that have identified low-molecular-weight inhibitors of IDPs. In addition, clinically relevant liquid–liquid phase separations—which critically involve both intermolecular interactions between IDPs and their posttranslational modification—are analyzed to understand the potential of IDPs as new drug targets.

Topological frustration leading to backtracking in a coupled folding-binding process

2021 ◽  
Author(s):  
Meng Gao ◽  
Ping Li ◽  
Zhengding Su ◽  
Yongqi Huang
Keyword(s):  
Structure Function ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Biological Processes ◽  
Sequence Structure ◽  
Binding Process ◽  
Intrinsically Disordered

Intrinsically disordered proteins (IDPs) are abundant in all species. Their discovery challenges the traditional “sequence−structure−function” paradigm of protein science, because IDPs play important roles in various biological processes without preformed...

scholarly journals Towards Targeting the Disordered SARS-CoV-2 Nsp2 C-terminal Region: Partial Structure and Dampened Mobility Revealed by NMR Spectroscopy

2020 ◽  
Author(s):  
Miguel Mompeán ◽  
Miguel Á. Treviño ◽  
Douglas V. Laurents
Keyword(s):  
Nmr Spectroscopy ◽  
Drug Targets ◽  
Intrinsically Disordered Proteins ◽  
Small Population ◽  
Terminal Region ◽  
Disordered Proteins ◽  
X Ray Crystallography ◽  
Intrinsically Disordered ◽  
Level Information ◽  
Human Proteins

AbstractIntrinsically disordered proteins (IDPs) play essential roles in regulating physiological processes in eukaryotic cells. Many virus use their own IDPs to “hack” these processes to disactive host defenses and promote viral growth. Thus, viral IDPs are attractive drug targets. While IDPs are hard to study by X-ray crystallography or cryo-EM, atomic level information on their conformational perferences and dynamics can be obtained using NMR spectroscopy. SARS-CoV-2 Nsp2 interacts with human proteins that regulate translation initiation and endosome vesicle sorting, and the C-terminal region of this protein is predicted to be disordered. Molecules that block these interactions could be valuable leads for drug development. To enable inhibitor screening and to uncover conformational preferences and dynamics, we have expressed and purified the 13C,15N-labeled C-terminal region of Nsp2. The 13Cβ and backbone 13CO, 1HN, 13Cα and 15N nuclei were assigned by analysis of a series of 2D 1H-15N HSQC and 13C-15N CON as well as 3D HNCO, HNCA, CBCAcoNH and HncocaNH spectra. Overall, the chemical shift data confirm that this region is chiefly disordered, but contains two five-residue segments that adopt a small population of β-strand structure. Whereas the region is flexible on ms/ms timescales as gauged by T1ρ measurements, the {1H}-15N NOEs reveal a flexibility on ns/ps timescales that is midway between a fully flexible and a completely rigid chain.

scholarly journals Germ Granules Coordinate RNA-based Epigenetic Inheritance Pathways

2019 ◽  
Author(s):  
Anne E. Dodson ◽  
Scott Kennedy
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Epigenetic Inheritance ◽  
Disordered Proteins ◽  
Wild Type ◽  
Granule Formation ◽  
Phase Separations ◽  
C Elegans ◽  
Intrinsically Disordered ◽  
Germ Granules ◽  
Systemic Rnai

AbstractGerm granules are biomolecular condensates that promote germ cell totipotency in most, if not all, animals. In C. elegans, MEG-3 and MEG-4 are two intrinsically disordered proteins that are redundantly required for the phase separations that drive germ granule assembly in germline blastomeres. Here, we show that animals lacking MEG-3/4 exhibit defects in dsRNA-mediated gene silencing (RNAi) that are due, at least in part, to defects in systemic RNAi. Interestingly, these RNAi defects are transgenerationally disconnected from meg-3/4 genotype: RNAi defects do not arise until 5-9 generations after animals become mutant for meg-3/4, and RNAi defects persist for 9-11 generations after meg-3/4 genotype is restored to wild type. Similar non-Mendelian patterns of inheritance are associated with other mutations that disrupt germ granule formation, indicating that germ granule disruption is the likely cause of genotype/phenotype disconnects. Loss of germ granules is associated with the production of aberrant populations of endogenous siRNAs, which, remarkably, are propagated for ≅10 generations in wild-type descendants of animals that lacked germ granules. sid-1, which encodes a factor required for systemic RNAi in C. elegans, is inappropriately and heritably silenced by aberrantly expressed sid-1 endogenous siRNAs, suggesting that transgenerational silencing of sid-1 likely underlies the heritable defect in RNAi. We conclude that one function of germ granules is to organize RNA-based epigenetic inheritance pathways and that failure to assemble germ granules has consequences that persist across many generations.

scholarly journals Therapeutic Interventions of Cancers Using Intrinsically Disordered Proteins as Drug Targets: c-Myc as Model System

2017 ◽  
Vol 16 ◽  
pp. 117693511769940 ◽  
Author(s):  
Deepak Kumar ◽  
Nitin Sharma ◽  
Rajanish Giri
Keyword(s):  
Drug Targets ◽  
Intrinsically Disordered Proteins ◽  
Hot Spot ◽  
Intrinsic Disorder ◽  
Therapeutic Interventions ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
In Vivo Experiments

The concept of protein intrinsic disorder has taken the driving seat to understand regulatory proteins in general. Reports suggest that in mammals nearly 75% of signalling proteins contain long disordered regions with greater than 30 amino acid residues. Therefore, intrinsically disordered proteins (IDPs) have been implicated in several human diseases and should be considered as potential novel drug targets. Moreover, intrinsic disorder provides a huge multifunctional capability to hub proteins such as c-Myc and p53. c-Myc is the hot spot for understanding and developing therapeutics against cancers and cancer stem cells. Our past understanding is mainly based on in vitro and in vivo experiments conducted using c-Myc as whole protein. Using the reductionist approach, c-Myc oncoprotein has been divided into structured and disordered domains. A wealth of data is available dealing with the structured perspectives of c-Myc, but understanding c-Myc in terms of disordered domains has just begun. Disorderness provides enormous flexibility to proteins in general for binding to numerous partners. Here, we have reviewed the current progress on understanding c-Myc using the emerging concept of IDPs.

scholarly journals SUMO: Glue or Solvent for Phase-Separated Ribonucleoprotein Complexes and Molecular Condensates?

2021 ◽  
Vol 8 ◽  
Author(s):  
Jan Keiten-Schmitz ◽  
Linda Röder ◽  
Eran Hornstein ◽  
Michaela Müller-McNicoll ◽  
Stefan Müller
Keyword(s):  
Spatial Organization ◽  
Intrinsically Disordered Proteins ◽  
Nuclear Bodies ◽  
Disordered Proteins ◽  
Cellular Processes ◽  
Cell Dysfunction ◽  
Intrinsically Disordered ◽  
Ribonucleoprotein Complexes ◽  
Pml Nuclear Bodies ◽  
Splicing Speckles

Spatial organization of cellular processes in membranous or membrane-less organelles (MLOs, alias molecular condensates) is a key concept for compartmentalizing biochemical pathways. Prime examples of MLOs are the nucleolus, PML nuclear bodies, nuclear splicing speckles or cytosolic stress granules. They all represent distinct sub-cellular structures typically enriched in intrinsically disordered proteins and/or RNA and are formed in a process driven by liquid-liquid phase separation. Several MLOs are critically involved in proteostasis and their formation, disassembly and composition are highly sensitive to proteotoxic insults. Changes in the dynamics of MLOs are a major driver of cell dysfunction and disease. There is growing evidence that post-translational modifications are critically involved in controlling the dynamics and composition of MLOs and recent evidence supports an important role of the ubiquitin-like SUMO system in regulating both the assembly and disassembly of these structures. Here we will review our current understanding of SUMO function in MLO dynamics under both normal and pathological conditions.

Sign in / Sign up

Export Citation Format

Share Document