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

Fu, L.; Cheng, S.; Riedel, D.; Kopecny, L.; Schuh, M.; Görlich, D.

doi:10.1101/2025.03.13.643050

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bioRxiv · 10.1101/2025.03.13.643050

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

Fu, L.·Cheng, S.·Riedel, D.·Kopecny, L.·Schuh, M.·Görlich, D.

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Abstract

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 capsids 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.

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Fu, L., Cheng, S., Riedel, D., Kopecny, L., Schuh, M., Görlich, D.. 2025-03-13. Governed by surface amino acid composition: HIV capsid passage through the NPC barrier. https://doi.org/10.1101/2025.03.13.643050

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