scholarly journals Mutations in disordered regions cause disease by creating endocytosis motifs

2017 ◽  
Author(s):  
Katrina Meyer ◽  
Bora Uyar ◽  
Marieluise Kirchner ◽  
Jingyuan Cheng ◽  
Altuna Akalin ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Wide Spectrum ◽  
Transmembrane Proteins ◽  
Dimensional Structure ◽  
Systematic Analysis ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Dileucine Motif ◽  
The Impact ◽  
Disordered Regions

AbstractMutations in intrinsically disordered regions (IDRs) of proteins can cause a wide spectrum of diseases. Since IDRs lack a fixed three-dimensional structure, the mechanism by which such mutations cause disease is often unknown. Here, we employ a proteomic screen to investigate the impact of mutations in IDRs on protein-protein interactions. We find that mutations in disordered cytosolic regions of three transmembrane proteins (GLUT1, ITPR1 and CACNA1H) lead to an increased binding of clathrins. In all three cases, the mutation creates a dileucine motif known to mediate clathrin-dependent trafficking. Follow-up experiments on GLUT1 (SLC2A1), a glucose transporter involved in GLUT1 deficiency syndrome, revealed that the mutated protein mislocalizes to intracellular compartments. A systematic analysis of other known disease-causing variants revealed a significant and specific overrepresentation of gained dileucine motifs in cytosolic tails of transmembrane proteins. Dileucine motif gains thus appear to be a recurrent cause of disease.

scholarly journals The Participation of the Intrinsically Disordered Regions of the bHLH-PAS Transcription Factors in Disease Development

2021 ◽  
Vol 22 (6) ◽  
pp. 2868
Author(s):  
Marta Kolonko-Adamska ◽  
Vladimir N. Uversky ◽  
Beata Greb-Markiewicz
Keyword(s):  
Transcription Factors ◽  
Phase Separation ◽  
Posttranslational Modifications ◽  
Wide Spectrum ◽  
In Silico Analysis ◽  
Missense Mutations ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Wide Range ◽  
Disordered Regions

The basic helix–loop–helix/Per-ARNT-SIM (bHLH-PAS) proteins are a family of transcription factors regulating expression of a wide range of genes involved in different functions, ranging from differentiation and development control by oxygen and toxins sensing to circadian clock setting. In addition to the well-preserved DNA-binding bHLH and PAS domains, bHLH-PAS proteins contain long intrinsically disordered C-terminal regions, responsible for regulation of their activity. Our aim was to analyze the potential connection between disordered regions of the bHLH-PAS transcription factors, post-transcriptional modifications and liquid-liquid phase separation, in the context of disease-associated missense mutations. Highly flexible disordered regions, enriched in short motives which are more ordered, are responsible for a wide spectrum of interactions with transcriptional co-regulators. Based on our in silico analysis and taking into account the fact that the functions of transcription factors can be modulated by posttranslational modifications and spontaneous phase separation, we assume that the locations of missense mutations inducing disease states are clearly related to sequences directly undergoing these processes or to sequences responsible for their regulation.

scholarly journals shiny-pred: a server for the prediction of protein disordered regions

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 230
Author(s):  
Mauricio Oberti ◽  
Iosif Vaisman
Keyword(s):  
Web Application ◽  
Intrinsically Disordered Proteins ◽  
Sequence Data ◽  
Disordered Proteins ◽  
Dimensional Structure ◽  
Protein Chain ◽  
Neural Network Models ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disordered Regions

Intrinsically disordered proteins or intrinsically disordered regions (IDR) are segments within a protein chain lacking a stable three-dimensional structure under normal physiological conditions. Accurate prediction of IDRs is challenging due to their genome wide occurrence and low ratio of disordered residues, making them a difficult target for traditional classification techniques. Existing computational methods mostly rely on sequence profiles to improve accuracy, which is time consuming and computationally expensive. The shiny-pred application is an ab initio sequence-only disorder predictor implemented in R/Shiny language. In order to make predictions, it uses convolutional neural network models, trained using PDB sequence data. It can be installed on any operating system on which R can be installed and run locally. A public version of the web application can be accessed at https://gmu-binf.shinyapps.io/shiny-pred

scholarly journals MemDis: Predicting Disordered Regions in Transmembrane Proteins

2021 ◽  
Vol 22 (22) ◽  
pp. 12270
Author(s):  
Laszlo Dobson ◽  
Gábor E. Tusnády
Keyword(s):  
Short Term Memory ◽  
Transmembrane Proteins ◽  
Chemical Properties ◽  
Prediction Method ◽  
Transport Processes ◽  
Prediction Methods ◽  
X Ray Crystallography ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disordered Regions

Transmembrane proteins (TMPs) play important roles in cells, ranging from transport processes and cell adhesion to communication. Many of these functions are mediated by intrinsically disordered regions (IDRs), flexible protein segments without a well-defined structure. Although a variety of prediction methods are available for predicting IDRs, their accuracy is very limited on TMPs due to their special physico-chemical properties. We prepared a dataset containing membrane proteins exclusively, using X-ray crystallography data. MemDis is a novel prediction method, utilizing convolutional neural network and long short-term memory networks for predicting disordered regions in TMPs. In addition to attributes commonly used in IDR predictors, we defined several TMP specific features to enhance the accuracy of our method further. MemDis achieved the highest prediction accuracy on TMP-specific dataset among other popular IDR prediction methods.

scholarly journals The Participation of the Intrinsically Disordered Regions of the bHLH-PAS Transcription Factors in Disease Development

2020 ◽  
Author(s):  
Beata Greb-Markiewicz ◽  
Marta Kolonko-Adamska
Keyword(s):  
Transcription Factors ◽  
Phase Separation ◽  
Wide Spectrum ◽  
In Silico Analysis ◽  
Activity Regulation ◽  
Missense Mutations ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Wide Range ◽  
Disordered Regions

The bHLH-PAS proteins are a family of transcription factors regulating expression of a wide range of genes involved in different functions, from differentiation and development control, by oxygen and toxins sensing to circadian clock setting. In addition to the well-preserved DNA-binding bHLH and PAS domains, bHLH-PAS proteins contain long intrinsically disordered C-terminal regions, responsible for their activity regulation. Our aim was to analyse the potential connection between disordered regions of the bHLH-PAS transcription factors with posttranscriptional modifications and liquid-liquid phase separation in the context of the disease-associated missense mutations. Highly flexible disordered regions, enriched in short more ordered motives, are responsible for wide spectrum of interactions with transcriptional co-regulators. Based on our in silico analysis and taking into account fact that transcription factors functions can be modulated by posttranslational modifications and spontaneous phase separation, we assume that the location of missense mutations inducing disease states, is clearly related to sequences directly undergoing these processes or to sequences responsible for their activity regulation.

scholarly journals The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease

2016 ◽  
Vol 44 (5) ◽  
pp. 1185-1200 ◽  
Author(s):  
M. Madan Babu
Keyword(s):  
Protein Function ◽  
Human Disease ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Sequence Structure ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
The 1960S ◽  
Functional Versatility ◽  
Disordered Regions

In the 1960s, Christian Anfinsen postulated that the unique three-dimensional structure of a protein is determined by its amino acid sequence. This work laid the foundation for the sequence–structure–function paradigm, which states that the sequence of a protein determines its structure, and structure determines function. However, a class of polypeptide segments called intrinsically disordered regions does not conform to this postulate. In this review, I will first describe established and emerging ideas about how disordered regions contribute to protein function. I will then discuss molecular principles by which regulatory mechanisms, such as alternative splicing and asymmetric localization of transcripts that encode disordered regions, can increase the functional versatility of proteins. Finally, I will discuss how disordered regions contribute to human disease and the emergence of cellular complexity during organismal evolution.

scholarly journals Analysis of structured and intrinsically disordered regions of transmembrane proteins

2009 ◽  
Vol 5 (12) ◽  
pp. 1688 ◽  
Author(s):  
Bin Xue ◽  
Liwei Li ◽  
Samy O. Meroueh ◽  
Vladimir N. Uversky ◽  
A. Keith Dunker
Keyword(s):  
Transmembrane Proteins ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disordered Regions
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