Nucleic acid chaperone activity of HIV-1 nucleocapsid protein: Critical role in reverse transcription and molecular mechanism

The HIV-1 nucleocapsid protein (NC) is a short, basic, nucleic-acid binding protein with two zinc finger domains, each containing the invariant CCHC metal ion binding motif. The mature protein (55 amino acid residues) is produced by proteolytic cleavage of the Gag precursor and is found in the interior of the virus particle, where it is tightly associated with genomic RNA. NC or the NC domain in Gag has multiple functions during the virus replication cycle, including genomic RNA packaging and virus assembly, primer placement on viral RNA, reverse transcription, and integration. Many of these functions rely on the nucleic acid chaperone activity of NC, i.e., the ability to catalyze nucleic acid conformational rearrangements that lead to the most thermodynamically stable structure. In this chapter, we focus on recent biochemical and biophysical studies that examine the nucleic acid chaperone function of HIV-1 NC and its critical role in facilitating specific and efficient reverse transcription. We describe the effect of NC on individual steps in viral DNA synthesis and summarize what is known about NC structure, NC nucleic acid binding properties, and the contribution of the zinc fingers to chaperone activity. In addition, we discuss new evidence that provides a model to explain the mechanism of NCs nucleic acid chaperone activity at the molecular level.