Governed by surface amino acid composition: HIV capsid passage through the NPC barrier

Nuclear transport receptors (NTRs) carry cargo across the permeability barrier of nuclear pore complexes (NPCs) - an FG phase condensed from disordered but cohesive FG repeats. This phase repels ‘normal’ macromolecules but allows NTR passage. When HIV infects non-dividing cells, its capsid is transported into nuclei not like cargo but crosses NPCs like NTRs. We now uncovered the molecular determinants of the capsid’s NTR behavior: The FG-binding pocket is insufficient. Hexameric and pentameric capsomers contribute. The highly exposed outer capsid surface is key. It lacks ‘FG-repulsive’ charged residues (K,D,E) that are very abundant on ‘normal’ protein surfaces. ‘FG-attractive’ residues dominate the capsid surface. Introducing FG-repulsive ones impedes FG phase-partitioning, NPC-targeting and NPC-passage of assembled capsids. Capsids are thus made FG phase-soluble by myriads of transient FG-attractive interactions originating from individual surface sidechains. We discuss that CPSF6 releases the capsid from NPCs by switching its surface from FG-attractive to FG-repulsive.