Prevalence and functionality of intrinsic disorder in human FG-nucleoporins

The nuclear-cytoplasmic transport of biomolecules is assisted by the nuclear pores composed of evolutionarily conserved proteins termed nucleoporins (Nups). The central Nups, characterized by multiple FG-repeats, are highly dynamic and contain a high level of intrinsically disordered regions (IDPRs). FG-Nups bind several protein partners and play critical roles in molecular interactions and the regulation of cellular functions through their IDPRs. In the present study, we performed a multiparametric bioinformatics analysis to characterize the prevalence and functionality of IDPRs in human FG-Nups. These analyses revealed that the sequence of all FG-Nups contained >50% IDPRs (except Nup54 and Nup358). Nup98, Nup153, and POM121 were extremely disordered with similar to 80% IDPRs. The functional disorder-based binding regions in the FG-Nups were identified. The phase separation behavior of FG-Nups indicated that all FG-Nups have the potential to undergo liquid-to-liquid phase separation that could stabilize their liquid state.The inherent structural flexibility in FG-Nups is mechanistically and functionally advantageous. Since certain FG-Nups interact with disease-relevant protein aggregates, their complexes can be exploited for drug design. Furthermore, consideration of the FG-Nups from the intrinsic disorder perspective provides critical information that can guide future experimental studies to uncover novel pathways associated with diseases linked with protein misfolding and aggregation. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

The nuclear pores composed of nucleoporins play critical roles in the nuclear-cytoplasmic transport of biomolecules. The high level of intrinsically disordered regions (IDPRs) in FG-Nups allows them to bind multiple protein partners and undergo liquid-to-liquid phase separation. This structural flexibility in FG-Nups is advantageous and can be exploited for drug design, especially in diseases associated with protein misfolding and aggregation.