Non-globular domains in human diseases

Non-globular proteins (NGPs) encompass diverse molecular phenomena that challenge the traditional sequence-structure-function paradigm, including intrinsically disordered regions, tandem repeats, aggregating domains, low-complexity sequences, and transmembrane domains. While NGPs are implicated in numerous human diseases (neurodegenerative disorders, cancers, etc), progress in predicting and assessing mutations affecting non-globular regions has been hindered by the lack of a systematic approach. Most computational methods for predicting variant pathogenicity are tailored to folded protein domains, limiting their applicability to NGPs.

Our primary objective is to characterize how mutations associated with human diseases impact the function of intrinsically disordered regions (IDRs). By investigating how these mutations modify IDR behavior and functionality, we aim to deepen our understanding of their role in disease pathology. This includes analyzing the structural and functional consequences of specific mutations and examining how these alterations influence overall protein behavior and cellular processes. Additionally, we seek to elucidate the relationship between IDR sequence, conformational diversity, and function—understanding how IDR amino acid sequences dictate their range of conformations and how genetic variants affect their functional roles.

Furthermore, we harness the growing wealth of human genetic data to identify disordered protein regions under evolutionary selection. This approach can uncover new mechanistic insights into how IDRs regulate cellular functions and how mutations disrupt these processes, thereby contributing to disease onset. Through these endeavors, we aim to bridge the gap between genetic mutations and their mechanistic impacts on IDRs, ultimately facilitating the development of novel diagnostic and therapeutic strategies for a range of diseases.

More in depth:
Neurodevelopmental Disorders