Computational Charachterization of FUS Disassembly by Kapb2

Abstract

Fused in Sarcoma (FUS) are RNA binding proteins the help regulate gene expression through transcription and mRNA transport. FUS are known to have prion-like domains which can transition from a liquid state to fibril-containing hydrogel which drives the pathological aggregation of FUS in cytoplasmic regions. Recent experimental studies have shown that the nuclear import receptor Karyopherin-β2 (Kapb2) can disassemble these aggregates through engagement of the nuclear localization signal (NLS) domain of FUS. The aim of this study is to computationally characterize FUS and Kapb2 structure, dynamics, interactions and disassembly mechanisms through the use of elastic network models and molecular dynamics simulation. This knowledge will yield the ability to systematically test combinations of mutant Kapb2 and FUS via computational simulation. Considering mutants of Kapb2 will help to identify the ideal candidates for disassembly across the mutants of FUS. This has implications for understanding disease mechanisms: FUS and its mutants have been linked to various neurodegenerative disorders such as ALS - a disease by which FUS aggregation in neurons lead to cell death and loss of muscle control. Thus, this study will help to identify the type of Kapb2 which will best treat FUS aggregation for different neurodegenerative disorders.