CPSF6 assembly dynamics and binding avidity on HIV-1 capsid are regulated by interactions between prion-like low complexity regions.

Abstract

The cleavage and polyadenylation specificity factor 6 (CPSF6) is a cellular protein that play crucial role in HIV-1 capsid nuclear entry. Higher-ordered oligomerization of CPSF6 forms string-like assemblies templated by the viral capsid lattice, despite low affinity of the CA-binding FG peptide of CPSF6. Structural studies revealed that multivalent CPSF6 assembly is mediated by interactions between prion-like low complexity regions (LCR), which are templated by binding of CPSF6 FG peptides to the CA monomer. In this work, we elucidate the CPSF6 assembly dynamical mechanism, specifically how FG-CA and LCR-LCR interactions work in concert to drive CPSF6 oligomerization on the HIV-1 capsid lattice. We first develop “bottom-up” coarse-grained (CG) model of CPSF6-CA and CPSF6-CPSF6 molecular interactions from atomistic simulation of a tri-CPSF6 complex complexed to 4 CA hexamers. Our simulations demonstrate that weakening the interactions between the low-complexity region of CPSF6 not only abrogates CPSF6 assembly but also weakens the binding avidity of the FG peptide to the CA binding pocket. The assembled CPSF6 oligomers are highly diffusive on the CA lattice exhibiting an ensemble of conformations, typical of unstructured proteins. At the high curvature region of the capsid lattice the string-like assemblies of CPSF6 appears to be disrupted. Our findings elucidate a network of interactions that regulate the CPSF6 assembly templated by the viral capsid lattice.