(A) NIRs like Kapβ2 (PDB: 4FDD) share a similar structure, with roughly 20 paired helical HEAT repeats coiled into an alpha solenoid structure. HEAT repeats comprise an outer helix (raspberry) and an inner, cargo-facing helix (blue; FUS-PY-NLS cargo, black). NIRs interact with cargo via two non-exclusive mechanisms. (B) Many NIRs will specifically interact with cargo bearing an NLS. For example, Kapβ2 (PDB: 4FDD) will interact with cargo bearing a PY-NLS, like FUS and hnRNPA1. (C) NIRs can also bind to cargo through additional or alternative interactions, including cation-π, π-π, and electrostatic interactions. Such interactions can occur with cargo that bears an NLS, and with cargo that has no known NLS sequence, such as the arginine-rich DPRs produced in c9ALS/FTD.