Structural model of the Rev regulatory protein from equine infectious anemia virus.
Rev is an essential regulatory protein in the equine infectious anemia virus (EIAV) and other lentiviruses, including HIV-1. It binds incompletely spliced viral mRNAs and shuttles them from the nucleus to the cytoplasm, a critical prerequisite for the production of viral structural proteins and genomic RNA. Despite its important role in production of infectious virus, the development of antiviral therapies directed against Rev has been hampered by the lack of an experimentally-determined structure of the full length protein. We have used a combined computational and biochemical approach to generate and evaluate a structural model of the Rev protein. The modeled EIAV Rev (ERev) structure includes a total of 6 helices, four of which form an anti-parallel four-helix bundle. The first helix contains the leucine-rich nuclear export signal (NES). An arginine-rich RNA binding motif, RRDRW, is located in a solvent-exposed loop region. An ERLE motif required for Rev activity is predicted to be buried in the core of modeled structure where it plays an essential role in stabilization of the Rev fold. This structural model is supported by existing genetic and functional data as well as by targeted mutagenesis of residues predicted to be essential for overall structural integrity. Our predicted structure should increase understanding of structure-function relationships in Rev and may provide a basis for the design of new therapies for lentiviral diseases.
Ihm
Yungok
Y
Department of Physics and Astronomy, Iowa State University, Ames, IA, USA. yihm@spring8.or.jp
Sparks
Wendy O
WO
Lee
Jae-Hyung
JH
Cao
Haibo
H
Carpenter
Susan
S
Wang
Cai-Zhuang
CZ
Ho
Kai-Ming
KM
Dobbs
Drena
D
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015694:Gene Products, rev / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006734:Horse Diseases; D006736:Horses / Q000382:microbiology; D004860:Infectious Anemia Virus, Equine / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008961:Models, Structural; D008969:Molecular Sequence Data; D016296:Mutagenesis; D017434:Protein Structure, Tertiary / Q000235:genetics; D013329:Structure-Activity Relationship
D015694:Gene Products, rev