scholarly journals Computational strategy for intrinsically disordered protein ligand design leads to the discovery of p53 transactivation domain I binding compounds that activate the p53 pathway

2021 ◽  
Author(s):  
Hao Ruan ◽  
Chen Yu ◽  
Xiaogang Niu ◽  
Weilin Zhang ◽  
Hanzhong Liu ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Ligand Design ◽  
Intrinsically Disordered Protein ◽  
Human Diseases ◽  
Disordered Proteins ◽  
Transactivation Domain ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Domain I ◽  
Computational Strategy

Intrinsically disordered proteins (IDPs) have gained much attention in recent years due to their vital roles in biology and prevalence in various human diseases. Although IDPs are perceived as attractive...

scholarly journals New technologies to analyse protein function: an intrinsic disorder perspective

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 101 ◽  
Author(s):  
Vladimir N. Uversky
Keyword(s):  
Protein Function ◽  
Intrinsically Disordered Proteins ◽  
New Technologies ◽  
Intrinsically Disordered Protein ◽  
Intrinsic Disorder ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Protein Functions ◽  
Require Structure

Functions of intrinsically disordered proteins do not require structure. Such structure-independent functionality has melted away the classic rigid “lock and key” representation of structure–function relationships in proteins, opening a new page in protein science, where molten keys operate on melted locks and where conformational flexibility and intrinsic disorder, structural plasticity and extreme malleability, multifunctionality and binding promiscuity represent a new-fangled reality. Analysis and understanding of this new reality require novel tools, and some of the techniques elaborated for the examination of intrinsically disordered protein functions are outlined in this review.

scholarly journals Phosphorylation regulates the binding of intrinsically disordered proteins via a flexible conformation selection mechanism

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Na Liu ◽  
Yue Guo ◽  
Shangbo Ning ◽  
Mojie Duan
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Hydrophobic Interactions ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Regulation Mechanism ◽  
Enhanced Sampling ◽  
Dynamic Interactions ◽  
Post Translational Modifications ◽  
Intrinsically Disordered ◽  
Disordered Protein

Abstract Phosphorylation is one of the most common post-translational modifications. The phosphorylation of the kinase-inducible domain (KID), which is an intrinsically disordered protein (IDP), promotes the folding of KID and binding with the KID-interacting domain (KIX). However, the regulation mechanism of the phosphorylation on KID is still elusive. In this study, the structural ensembles and binding process of pKID and KIX are studied by all-atom enhanced sampling technologies. The results show that more hydrophobic interactions are formed in pKID, which promote the formation of the special hydrophobic residue cluster (HRC). The pre-formed HRC promotes binding to the correct sites of KIX and further lead the folding of pKID. Consequently, a flexible conformational selection model is proposed to describe the binding and folding process of intrinsically disordered proteins. The binding mechanism revealed in this work provides new insights into the dynamic interactions and phosphorylation regulation of proteins.

scholarly journals The intrinsically disordered protein SPE-18 promotes localized assembly of the major sperm protein in C. elegans spermatocytes

2020 ◽  
Author(s):  
Kari L. Price ◽  
Marc Presler ◽  
Christopher M. Uyehara ◽  
Diane C. Shakes
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Major Sperm Protein ◽  
Sperm Protein ◽  
C Elegans ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Changing Patterns ◽  
Cytoskeletal Elements

ABSTRACTMany specialized cells use unconventional strategies of cytoskeletal control. Nematode spermatocytes discard their actin and tubulin following meiosis, and instead employ the regulated assembly/disassembly of the Major Sperm Protein (MSP) to drive sperm motility. However prior to the meiotic divisions, MSP is effectively sequestered as it exclusively assembles into paracrystalline structures called fibrous bodies (FBs). The accessory proteins that direct this sequestration process have remained mysterious. This study reveals SPE-18 as an intrinsically disordered protein that that is essential for MSP assembly within FBs. In spe-18 mutant spermatocytes, MSP remains cytosolic, and the cells arrest in meiosis. In wildtype spermatocytes, SPE-18 localizes to pre-FB complexes and functions with the kinase SPE-6 to recruit MSP. Changing patterns of SPE-18 localization revealed unappreciated complexities in FB maturation. Later, within newly individualized spermatids, SPE −18 is rapidly lost, yet SPE-18 loss alone is insufficient for MSP disassembly. Our findings reveal an alternative strategy for sequestering cytoskeletal elements, not as monomers but in localized, bundled polymers. Additionally, these studies provide an important example of disordered proteins promoting ordered cellular structures.Summary StatementIntrinsically disordered proteins are increasingly recognized as key regulators of localized cytoskeletal assembly. Expanding that paradigm, SPE-18 localizes MSP assembly within C. elegans spermatocytes.

scholarly journals Degradation of Intrinsically Disordered Proteins by the NADH 26S Proteasome

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1642
Author(s):  
Peter Tsvetkov ◽  
Nadav Myers ◽  
Julia Adler ◽  
Yosef Shaul
Keyword(s):  
Substrate Specificity ◽  
Structural Integrity ◽  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Degradation Pathway ◽  
26S Proteasome ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Disordered Protein

The 26S proteasome is the endpoint of the ubiquitin- and ATP-dependent degradation pathway. Over the years, ATP was regarded as completely essential for 26S proteasome function due to its role in ubiquitin-signaling, substrate unfolding and ensuring its structural integrity. We have previously reported that physiological concentrations of NADH are efficient in replacing ATP to maintain the integrity of an enzymatically functional 26S PC. However, the substrate specificity of the NADH-stabilized 26S proteasome complex (26S PC) was never assessed. Here, we show that the binding of NADH to the 26S PC inhibits the ATP-dependent and ubiquitin-independent degradation of the structured ODC enzyme. Moreover, the NADH-stabilized 26S PC is efficient in degrading intrinsically disordered protein (IDP) substrates that might not require ATP-dependent unfolding, such as p27, Tau, c-Fos and more. In some cases, NADH-26S proteasomes were more efficient in processing IDPs than the ATP-26S PC. These results indicate that in vitro, physiological concentrations of NADH can alter the processivity of ATP-dependent 26S PC substrates such as ODC and, more importantly, the NADH-stabilized 26S PCs promote the efficient degradation of many IDPs. Thus, ATP-independent, NADH-dependent 26S proteasome activity exemplifies a new principle of how mitochondria might directly regulate 26S proteasome substrate specificity.

scholarly journals Proteasomal degradation of the intrinsically disordered protein tau at single-residue resolution

2020 ◽  
Vol 6 (30) ◽  
pp. eaba3916 ◽  
Author(s):  
T. Ukmar-Godec ◽  
P. Fang ◽  
A. Ibáñez de Opakua ◽  
F. Henneberg ◽  
A. Godec ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Degradation Products ◽  
Degradation Kinetics ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Dependent Protein Kinase ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Dependent Protein ◽  
Independent Process

Intrinsically disordered proteins (IDPs) can be degraded in a ubiquitin-independent process by the 20S proteasome. Decline in 20S activity characterizes neurodegenerative diseases. Here, we examine 20S degradation of IDP tau, a protein that aggregates into insoluble deposits in Alzheimer’s disease. We show that cleavage of tau by the 20S proteasome is most efficient within the aggregation-prone repeat region of tau and generates both short, aggregation-deficient peptides and two long fragments containing residues 1 to 251 and 1 to 218. Phosphorylation of tau by the non-proline–directed Ca2+/calmodulin-dependent protein kinase II inhibits degradation by the 20S proteasome. Phosphorylation of tau by GSK3β, a major proline-directed tau kinase, modulates tau degradation kinetics in a residue-specific manner. The study provides detailed insights into the degradation products of tau generated by the 20S proteasome, the residue specificity of degradation, single-residue degradation kinetics, and their regulation by posttranslational modification.

scholarly journals Modelling Intrinsically Disordered Protein Dynamics as Networks of Transient Secondary Structure

2018 ◽  
Author(s):  
Hannah K. Wayment-Steele ◽  
Carlos X. Hernández ◽  
Vijay S. Pande
Keyword(s):  
Secondary Structure ◽  
Intrinsically Disordered Proteins ◽  
Model Building ◽  
Intrinsically Disordered Protein ◽  
Dynamics Simulation ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
State Models ◽  
Transient Secondary Structure

ABSTRACTDescribing the dynamics and conformational landscapes of Intrinsically Disordered Proteins (IDPs) is of paramount importance to understanding their functions. Markov State Models (MSMs) are often used to characterize the dynamics of more structured proteins, but models of IDPs built using conventional MSM modelling protocols can be difficult to interpret due to the inherent nature of IDPs, which exhibit fast transitions between disordered microstates. We propose a new method of determining MSM states from all-atom molecular dynamics simulation data of IDPs by using per-residue secondary structure assignments as input features in a MSM model. Because such secondary structure algorithms use a select set of features for assignment (dihedral angles, contact distances, etc.), they represent a knowledge-based refinement of feature sets used for model-building. This method adds interpretability to IDP conformational landscapes, which are increasingly viewed as composed of transient secondary structure, and allows us to readily use MSM analysis tools in this paradigm. We demonstrate the use of our method with the transcription factor p53 c-terminal domain (p53-CTD), a commonly-studied IDP. We are able to characterize the full secondary structure phase space observed for p53-CTD, and describe characteristics of p53-CTD as a network of transient helical and beta-hairpin structures with different network behaviors in different domains of secondary structure. This analysis provides a novel example of how IDPs can be studied and how researchers might better understand a disordered protein conformational landscape.

scholarly journals RFPR-IDP: reduce the false positive rates for intrinsically disordered protein and region prediction by incorporating both fully ordered proteins and disordered proteins

2020 ◽  
Author(s):  
Yumeng Liu ◽  
Xiaolong Wang ◽  
Bin Liu
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Short Term Memory ◽  
Protein Structures ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Test Dataset ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Real World Applications ◽  
Long Short Term Memory

Abstract As an important type of proteins, intrinsically disordered proteins/regions (IDPs/IDRs) are related to many crucial biological functions. Accurate prediction of IDPs/IDRs is beneficial to the prediction of protein structures and functions. Most of the existing methods ignore the fully ordered proteins without IDRs during training and test processes. As a result, the corresponding predictors prefer to predict the fully ordered proteins as disordered proteins. Unfortunately, these methods were only evaluated on datasets consisting of disordered proteins without or with only a few fully ordered proteins, and therefore, this problem escapes the attention of the researchers. However, most of the newly sequenced proteins are fully ordered proteins in nature. These predictors fail to accurately predict the ordered and disordered proteins in real-world applications. In this regard, we propose a new method called RFPR-IDP trained with both fully ordered proteins and disordered proteins, which is constructed based on the combination of convolution neural network (CNN) and bidirectional long short-term memory (BiLSTM). The experimental results show that although the existing predictors perform well for predicting the disordered proteins, they tend to predict the fully ordered proteins as disordered proteins. In contrast, the RFPR-IDP predictor can correctly predict the fully ordered proteins and outperform the other 10 state-of-the-art methods when evaluated on a test dataset with both fully ordered proteins and disordered proteins. The web server and datasets of RFPR-IDP are freely available at http://bliulab.net/RFPR-IDP/server.

scholarly journals Computing, analyzing and comparing the radius of gyration and hydrodynamic radius in conformational ensembles of intrinsically disordered proteins

2019 ◽  
Author(s):  
Mustapha Carab Ahmed ◽  
Ramon Crehuet ◽  
Kresten Lindorff-Larsen
Keyword(s):  
Hydrodynamic Radius ◽  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Radius Of Gyration ◽  
Conformational Ensemble ◽  
Conformational Ensembles ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Nmr Diffusion

AbstractThe level of compaction of an intrinsically disordered protein may affect both its physical and biological properties, and can be probed via different types of biophysical experiments. Small-angle X-ray scattering (SAXS) probe the radius of gyration (Rg) whereas pulsed-field-gradient nuclear magnetic resonance (NMR) diffusion, fluorescence correlation spectroscopy and dynamic light scattering experiments can be used to determine the hydrodynamic radius (Rh). Here we show how to calculate Rg and Rh from a computationally-generated conformational ensemble of an intrinsically disordered protein. We further describe how to use a Bayesian/Maximum Entropy procedure to integrate data from SAXS and NMR diffusion experiments, so as to derive conformational ensembles in agreement with those experiments.

Monitoring structural changes in intrinsically disordered proteins using QCM-D: application to the bacterial cell division protein ZipA

2016 ◽  
Vol 52 (39) ◽  
pp. 6541-6544 ◽  
Author(s):  
Pablo Mateos-Gil ◽  
Achilleas Tsortos ◽  
Marisela Vélez ◽  
Electra Gizeli
Keyword(s):  
Cell Division ◽  
Structural Changes ◽  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Bacterial Cell Division ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Cell Division Protein

Characterization of structural changes in an intrinsically disordered protein attached on a QCM-D, with a sensitivity of 1.8 nm or better.

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