3lph | pdb_00003lph
Crystal structure of the HIV-1 Rev dimer
Structural highlights
Function[REV_HV1H3] Escorts unspliced or incompletely spliced viral pre-mRNAs (late transcripts) out of the nucleus of infected cells. These pre-mRNAs carry a recognition sequence called Rev responsive element (RRE) located in the env gene, that is not present in fully spliced viral mRNAs (early transcripts). This function is essential since most viral proteins are translated from unspliced or partially spliced pre-mRNAs which cannot exit the nucleus by the pathway used by fully processed cellular mRNAs. Rev itself is translated from a fully spliced mRNA that readily exits the nucleus. Rev's nuclear localization signal (NLS) binds directly to KPNB1/Importin beta-1 without previous binding to KPNA1/Importin alpha-1. KPNB1 binds to the GDP bound form of RAN (Ran-GDP) and targets Rev to the nucleus. In the nucleus, the conversion from Ran-GDP to Ran-GTP dissociates Rev from KPNB1 and allows Rev's binding to the RRE in viral pre-mRNAs. Rev multimerization on the RRE via cooperative assembly exposes its nuclear export signal (NES) to the surface. Rev can then form a complex with XPO1/CRM1 and Ran-GTP, leading to nuclear export of the complex. Conversion from Ran-GTP to Ran-GDP mediates dissociation of the Rev/RRE/XPO1/RAN complex, so that Rev can return to the nucleus for a subsequent round of export. Beside KPNB1, also seems to interact with TNPO1/Transportin-1, RANBP5/IPO5 and IPO7/RANBP7 for nuclear import. The nucleoporin-like HRB/RIP is an essential cofactor that probably indirectly interacts with Rev to release HIV RNAs from the perinuclear region to the cytoplasm.[1] [2] [3] Publication Abstract from PubMedHIV replication requires nuclear export of unspliced viral RNAs to translate structural proteins and package genomic RNA. Export is mediated by cooperative binding of the Rev protein to the Rev response element (RRE) RNA, to form a highly specific oligomeric ribonucleoprotein (RNP) that binds to the Crm1 host export factor. To understand how protein oligomerization generates cooperativity and specificity for RRE binding, we solved the crystal structure of a Rev dimer at 2.5-A resolution. The dimer arrangement organizes arginine-rich helices at the ends of a V-shaped assembly to bind adjacent RNA sites and structurally couple dimerization and RNA recognition. A second protein-protein interface arranges higher-order Rev oligomers to act as an adaptor to the host export machinery, with viral RNA bound to one face and Crm1 to another, the oligomers thereby using small, interconnected modules to physically arrange the RNP for efficient export. Structural basis for cooperative RNA binding and export complex assembly by HIV Rev.,Daugherty MD, Liu B, Frankel AD Nat Struct Mol Biol. 2010 Nov;17(11):1337-42. Epub 2010 Oct 17. PMID:20953181[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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