HIV-1 RNA dimerization is a complex process that involves a series of RNA refolding events. The monomeric RNA can adopt two alternative conformations that largely determine the efficiency of dimerization. The dimeric RNA also exists in two different conformations, an initial kissing-loop complex and a stable dimer with extended intermolecular base pairing. We describe an ordered RNA folding pathway that incorporates this multitude of HIV-1 RNA conformers. Analysis of mutant transcripts designed to block distinct steps of the refolding cascade supports this model. The folding properties of the wild-type RNA and the defects caused by the mutations can be fully understood in terms of the free energy changes associated with secondary structure rearrangements.
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