WP4
–
IDR in disease
Objectives
WP4 aims to investigate the involvement of IDRs in diseases, with the ultimate goal of providing data and tools for diagnosis and therapeutics. IDRs play critical roles in protein Liquid-Liquid Phase Separation (LLPS) and protein self- assembly, processes that have been implicated in a range of diseases, including neurodegenerative disorders. Therefore, these regions represent promising therapeutic targets for mitigating abnormal LLPS and protein aggregation, with initial therapeutic interventions already emerging. However, to effectively target these proteins/regions, proper identification and classification are essential.
In many cases, the onset, penetrance, or clinical severity of diseases relies on mutations occurring within the IDRs of proteins associated with these pathologies. Even in the absence of mutations, the aggregation of a specific protein can lead to different diseases or variations in the manifestation of the same disorder. This phenomenon is exemplified in neurodegenerative diseases, where amyloid structural polymorphism plays a central role in pathogenesis, clinical manifestation, and the spread of pathology, presenting a significant challenge for therapeutic interventions. Another independent way in which IDRs contribute to disease is through their involvement in host-parasite interactions, particularly through structural mimicry.
In this scenario, parasite IDPs adopt features of host proteins to subvert cellular processes. Additionally, IDPs aid in evading immune surveillance and establishing infection.
WP4 focuses on exploring the involvement of IDRs in disease pathology. Another objective of WP4 is to analyze IDRs as determinants of amyloid structural polymorphism and clinical phenotypes in neurodegenerative disorders.
Task list
Task 4.1 – IDR variations in diseases
Details
Task 4.1 aims to create a comprehensive catalogue of amino acid variations in IDRs that are implicated in diseases. The objective is to identify patterns related to diseases and uncover general trends that can inform genetic counselling. The mutations will be stored in a dedicated ClinVar catalogue, categorised based on different types of IDRs such as low complexity, prion-like domains, globular domains, motifs, among others. Additionally, the mutations will be annotated with predicted pathological roles and relevant metadata for further developments.
Task 4.2 – Disease-promoting IDRs detection
Details
Task 4.2 focuses on the development of new methods, leveraging AI-assisted approaches such as protein Language Models (pLMs), to predict proteins involved in Liquid-Liquid Phase Separation (LLPS). The task specifically targets LLPS-promoting proteins and aggregation-prone regions implicated in disease. The analysis will investigate the role of these regions in condensate formation; cellular structures such as the nucleolus, stress granules and the p-bodies), and the regulation of protein aggregation in pathology.
Task 4.3 – Identification and analysis of amyloid protein structures
Details
Task 4.3 aims to identify and analyse variations in amyloid protein structures to enable personalised medicine applications by targeting specific structural ensembles. The task focuses on creating a data repository of disordered amyloidogenic motifs in disease-associated proteins involved in amyloid structural polymorphism, brain amyloid propagation, and divergent disease severity. Additionally, tools will be developed to detect and rank these regions once they fold into amyloids using Cryo-EM structures.
Deliverables
Catalogue of amino acid variations in IDRs that are implicated in diseases
Dataset of amyloidogenic motifs in disease-associated proteins