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HIV Rev Assembly on the Rev Response Element (RRE): A Structural Perspective.

Rausch JW, Le Grice SF - Viruses (2015)

Bottom Line: Once in the cytoplasm, the complexes dissociate and unspliced and singly-spliced viral RNAs are packaged into nascent virions or translated into viral structural proteins and enzymes, respectively.Rev binding to the RRE is a complex process, as multiple copies of the protein assemble on the RNA in a coordinated fashion via a series of Rev-Rev and Rev-RNA interactions.Our understanding of the nature of these interactions has been greatly advanced by recent studies using X-ray crystallography, small angle X-ray scattering (SAXS) and single particle electron microscopy as well as biochemical and genetic methodologies.

View Article: PubMed Central - PubMed

Affiliation: Reverse Transcriptase Biochemistry Section, Basic Research Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. rauschj@mail.nih.gov.

ABSTRACT
HIV-1 Rev is an ~13 kD accessory protein expressed during the early stage of virus replication. After translation, Rev enters the nucleus and binds the Rev response element (RRE), a ~350 nucleotide, highly structured element embedded in the env gene in unspliced and singly spliced viral RNA transcripts. Rev-RNA assemblies subsequently recruit Crm1 and other cellular proteins to form larger complexes that are exported from the nucleus. Once in the cytoplasm, the complexes dissociate and unspliced and singly-spliced viral RNAs are packaged into nascent virions or translated into viral structural proteins and enzymes, respectively. Rev binding to the RRE is a complex process, as multiple copies of the protein assemble on the RNA in a coordinated fashion via a series of Rev-Rev and Rev-RNA interactions. Our understanding of the nature of these interactions has been greatly advanced by recent studies using X-ray crystallography, small angle X-ray scattering (SAXS) and single particle electron microscopy as well as biochemical and genetic methodologies. These advances are discussed in detail in this review, along with perspectives on development of antiviral therapies targeting the HIV-1 RRE.

No MeSH data available.


Related in: MedlinePlus

Three-dimensional models of the HIV-2 and HIV-1 RREs: (A) HIV-2 RRE model structure obtained using SHAPE and molecular modeling with RNA Composer. Substructures homologous to those reported for the HIV-1 RRE are indicated. The region of base pairing that bridges the gap between stem loops IV and V and the rest of the structure is also shown (Br, black ribbon); (B) A-like SAXS envelope obtained for a truncated HIV-1 RRE (233 nt). Sub-structure designations and positioning are determined by fitting an RRE molecular model into the SAXS envelope. The molecular model was generated using the RRE 4-stem secondary structure as a template. High-affinity Rev binding sites at IIB and IA are separated by approximately 55 Å.
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viruses-07-02760-f005: Three-dimensional models of the HIV-2 and HIV-1 RREs: (A) HIV-2 RRE model structure obtained using SHAPE and molecular modeling with RNA Composer. Substructures homologous to those reported for the HIV-1 RRE are indicated. The region of base pairing that bridges the gap between stem loops IV and V and the rest of the structure is also shown (Br, black ribbon); (B) A-like SAXS envelope obtained for a truncated HIV-1 RRE (233 nt). Sub-structure designations and positioning are determined by fitting an RRE molecular model into the SAXS envelope. The molecular model was generated using the RRE 4-stem secondary structure as a template. High-affinity Rev binding sites at IIB and IA are separated by approximately 55 Å.

Mentions: Thus far, molecular modeling and small angle X-ray scattering (SAXS) have been the only means of generating 3D models of the RRE. One option for the former approach is to use RNA Composer, a web-based RNA folding application that uses homology modeling and energy minimization to assemble a 3D RNA structure from primary sequence and an associated secondary structure map [50]. This software was used to generate the 3D model of the HIV-2 RRE depicted in Figure 5A [47]. While less is known about HIV-2 Rev assembly on its cognate RRE, alignment of the homologs of IIB, the central junction and stem loop I in this model suggest that the RRE 3D structures and mechanisms of Rev assembly may be similar between HIV-2 and HIV-1.


HIV Rev Assembly on the Rev Response Element (RRE): A Structural Perspective.

Rausch JW, Le Grice SF - Viruses (2015)

Three-dimensional models of the HIV-2 and HIV-1 RREs: (A) HIV-2 RRE model structure obtained using SHAPE and molecular modeling with RNA Composer. Substructures homologous to those reported for the HIV-1 RRE are indicated. The region of base pairing that bridges the gap between stem loops IV and V and the rest of the structure is also shown (Br, black ribbon); (B) A-like SAXS envelope obtained for a truncated HIV-1 RRE (233 nt). Sub-structure designations and positioning are determined by fitting an RRE molecular model into the SAXS envelope. The molecular model was generated using the RRE 4-stem secondary structure as a template. High-affinity Rev binding sites at IIB and IA are separated by approximately 55 Å.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488727&req=5

viruses-07-02760-f005: Three-dimensional models of the HIV-2 and HIV-1 RREs: (A) HIV-2 RRE model structure obtained using SHAPE and molecular modeling with RNA Composer. Substructures homologous to those reported for the HIV-1 RRE are indicated. The region of base pairing that bridges the gap between stem loops IV and V and the rest of the structure is also shown (Br, black ribbon); (B) A-like SAXS envelope obtained for a truncated HIV-1 RRE (233 nt). Sub-structure designations and positioning are determined by fitting an RRE molecular model into the SAXS envelope. The molecular model was generated using the RRE 4-stem secondary structure as a template. High-affinity Rev binding sites at IIB and IA are separated by approximately 55 Å.
Mentions: Thus far, molecular modeling and small angle X-ray scattering (SAXS) have been the only means of generating 3D models of the RRE. One option for the former approach is to use RNA Composer, a web-based RNA folding application that uses homology modeling and energy minimization to assemble a 3D RNA structure from primary sequence and an associated secondary structure map [50]. This software was used to generate the 3D model of the HIV-2 RRE depicted in Figure 5A [47]. While less is known about HIV-2 Rev assembly on its cognate RRE, alignment of the homologs of IIB, the central junction and stem loop I in this model suggest that the RRE 3D structures and mechanisms of Rev assembly may be similar between HIV-2 and HIV-1.

Bottom Line: Once in the cytoplasm, the complexes dissociate and unspliced and singly-spliced viral RNAs are packaged into nascent virions or translated into viral structural proteins and enzymes, respectively.Rev binding to the RRE is a complex process, as multiple copies of the protein assemble on the RNA in a coordinated fashion via a series of Rev-Rev and Rev-RNA interactions.Our understanding of the nature of these interactions has been greatly advanced by recent studies using X-ray crystallography, small angle X-ray scattering (SAXS) and single particle electron microscopy as well as biochemical and genetic methodologies.

View Article: PubMed Central - PubMed

Affiliation: Reverse Transcriptase Biochemistry Section, Basic Research Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. rauschj@mail.nih.gov.

ABSTRACT
HIV-1 Rev is an ~13 kD accessory protein expressed during the early stage of virus replication. After translation, Rev enters the nucleus and binds the Rev response element (RRE), a ~350 nucleotide, highly structured element embedded in the env gene in unspliced and singly spliced viral RNA transcripts. Rev-RNA assemblies subsequently recruit Crm1 and other cellular proteins to form larger complexes that are exported from the nucleus. Once in the cytoplasm, the complexes dissociate and unspliced and singly-spliced viral RNAs are packaged into nascent virions or translated into viral structural proteins and enzymes, respectively. Rev binding to the RRE is a complex process, as multiple copies of the protein assemble on the RNA in a coordinated fashion via a series of Rev-Rev and Rev-RNA interactions. Our understanding of the nature of these interactions has been greatly advanced by recent studies using X-ray crystallography, small angle X-ray scattering (SAXS) and single particle electron microscopy as well as biochemical and genetic methodologies. These advances are discussed in detail in this review, along with perspectives on development of antiviral therapies targeting the HIV-1 RRE.

No MeSH data available.


Related in: MedlinePlus