Distinct nucleic acid interaction properties of HIV-1 nucleocapsid protein precursor NCp15 explain reduced viral infectivity

Wei Wang, Nada Naiyer, Mithun Mitra, Jialin Li, Mark C. Williams, Ioulia Rouzina, Robert J. Gorelick, Zhengrong Wu, Karin Musier-Forsyth

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

During human immunodeficiency virus type 1 (HIV-1) maturation, three different forms of nucleocapsid (NC) protein-NCp15 (p9 + p6), NCp9 (p7 + SP2) and NCp7-appear successively. A mutant virus expressing NCp15 shows greatly reduced infectivity. Mature NCp7 is a chaperone protein that facilitates remodeling of nucleic acids (NAs) during reverse transcription. To understand the strict requirement for NCp15 processing, we compared the chaperone function of the three forms of NC. NCp15 anneals tRNA to the primer-binding site at a similar rate as NCp7, whereas NCp9 is the most efficient annealing protein. Assays to measure NA destabilization show a similar trend. Dynamic light scattering studies reveal that NCp15 forms much smaller aggregates relative to those formed by NCp7 and NCp9. Nuclear magnetic resonance studies suggest that the acidic p6 domain of HIV-1 NCp15 folds back and interacts with the basic zinc fingers. Neutralizing the acidic residues in p6 improves the annealing and aggregation activity of NCp15 to the level of NCp9 and increases the protein-NA aggregate size. Slower NCp15 dissociation kinetics is observed by single-molecule DNA stretching, consistent with the formation of electrostatic inter-protein contacts, which likely contribute to the distinct aggregate morphology, irregular HIV-1 core formation and non-infectious virus.

Original languageEnglish (US)
Pages (from-to)7145-7159
Number of pages15
JournalNucleic acids research
Volume42
Issue number11
DOIs
StatePublished - 2014

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    Wang, W., Naiyer, N., Mitra, M., Li, J., Williams, M. C., Rouzina, I., Gorelick, R. J., Wu, Z., & Musier-Forsyth, K. (2014). Distinct nucleic acid interaction properties of HIV-1 nucleocapsid protein precursor NCp15 explain reduced viral infectivity. Nucleic acids research, 42(11), 7145-7159. https://doi.org/10.1093/nar/gku335