Mutations of Intrinsically Disordered Protein Regions Can Drive Cancer but Lack Therapeutic Strategies.
Bálint Mészáros,Borbála Hajdu-Soltész,András Zeke,Zsuzsanna Dosztányi +3 more
- Vol. 11, Iss: 3, pp 381
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TLDR
In this article, the authors used an integrative computational approach to explore the direct role of intrinsically disordered protein regions driving cancer and found that around 20% of cancer drivers are primarily targeted through a disordered region.Abstract:
Many proteins contain intrinsically disordered regions (IDRs) which carry out important functions without relying on a single well-defined conformation. IDRs are increasingly recognized as critical elements of regulatory networks and have been also associated with cancer. However, it is unknown whether mutations targeting IDRs represent a distinct class of driver events associated with specific molecular and system-level properties, cancer types and treatment options. Here, we used an integrative computational approach to explore the direct role of intrinsically disordered protein regions driving cancer. We showed that around 20% of cancer drivers are primarily targeted through a disordered region. These IDRs can function in multiple ways which are distinct from the functional mechanisms of ordered drivers. Disordered drivers play a central role in context-dependent interaction networks and are enriched in specific biological processes such as transcription, gene expression regulation and protein degradation. Furthermore, their modulation represents an alternative mechanism for the emergence of all known cancer hallmarks. Importantly, in certain cancer patients, mutations of disordered drivers represent key driving events. However, treatment options for such patients are currently severely limited. The presented study highlights a largely overlooked class of cancer drivers associated with specific cancer types that need novel therapeutic options.read more
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On the Potential of Machine Learning to Examine the Relationship Between Sequence, Structure, Dynamics and Function of Intrinsically Disordered Proteins
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From the Evasion of Degradation to Ubiquitin-Dependent Protein Stabilization
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Intrinsically Disordered Proteins: An Overview
TL;DR: A review on different aspects of disordered proteins and disordered protein regions, which form the basis of the so-called "disorder-function paradigm" of proteins is presented in this article .
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Biological soft matter: intrinsically disordered proteins in liquid–liquid phase separation and biomolecular condensates
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Book ChapterDOI
Functions of intrinsically disordered proteins through evolutionary lenses.
TL;DR: In this article, the authors give an overview of the different types of evolutionary behavior of disordered proteins and associated functions in normal and disease settings in both disease and normal settings. But, different evolutionary rules apply for the group of intrinsically disordered regions and proteins (IDR/IDPs) that exist as an ensemble of fluctuating conformations.
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TL;DR: The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA with a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages.