A long-awaited structure is rev-ealed

Abstract

It has been known for some time that the HIV Rev protein binds and oligomerizes on a well-defined multiple stem-loop RNA structure, named the Rev Response Element (RRE), which is present in a subset of HIV mRNAs. This binding is the first step in a pathway that overcomes a host restriction, which would otherwise prevent the export of these RNAs to the cytoplasm. Four recent publications now provide new insight into the structure of Rev and the multimeric RNA-protein complex that forms on the RRE. Two unexpected and remarkable findings revealed in these studies are the flexibility of RNA binding that is demonstrated by the Rev arginine-rich RNA binding motif, and the way that both Rev protein and RRE contribute to the formation of the complex in a highly cooperative fashion. These studies also define the Rev dimerization and oligomerization interfaces to a resolution of 2.5Å, providing a framework necessary for further structural and functional studies. Additionally, and perhaps most importantly, they also pave the way for rational drug design, which may ultimately lead to new therapies to inhibit this essential HIV function.

Keywords: HIV-1; RNA export; RNA-protein binding; RRE; Rev; X-ray crystallography; nuclear-cytoplasmic export; protein structure.

Figure 1

Structure of the Rev Dimer. (a) Two views of a surface representation of dimer are shown. (b) The folded core of a Rev monomer with its functional domains highlighted is shown. The amino acids prominent in mediating the core structure are specified. The different colors of the ribbon indicate amino acid conservation among 1201 HIV-1 isolates in the Los Alamos Sequence Database, with green representing the least conservation (26%) and red the highest (100%). Reprinted with permission from Macmillan Publishers Ltd: Nature Structural & Molecular Biology 17, 1337–1342 (2010) [3].

Figure 2

Model of the Rev dimer interacting with a model Rev Response Element (RRE) stem IIB binding site. In this model, the second monomer binds cooperatively using a different surface of the arginine rich helical motif (ARM) to contact the RNA (red). The yellow residue in the diagram represents Asn40 which contacts the RNA on the “inner face” of ARM1 but not ARM2 which uses the “outer face” of the ARM to bind. Reprinted with permission from Macmillan Publishers Ltd: Nature Structural & Molecular Biology 17, 1337–1342 (2010) [3].