Rev (HIV)
REV protein bound to RRE mRNA | |||||||||
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Rev is a transactivating
History
A novel protein was found to be involved in the translation of gag and env mRNA. The unknown protein functioned by removing repression of regulatory sequences and was named Art (anti-repression transactivator).[1] Later studies suggested that the protein was involved in regulation of the RNA splicing mechanism. Therefore, the name of the protein was modified from Art to Trs (transregulator of splicing).[2] The most recent studies have shown that the protein has multiple functions in the regulation of HIV-1 proteins, and its name has been changed to Rev (regulator of expression of virion proteins), which more generally describes its function.[3]
Structure
Rev is a 13-kDa protein[4] that is composed of 116 amino acids.[5] Rev's sequence contains two specific domains which contribute to its nuclear import and export. The protein typically performs its function as a tetramer.[citation needed]
Arginine-rich motif
The
Rev-activation domain (Nuclear export signal)
Rev's
Function
HIV-1 regulatory proteins (including Rev) are translated from completely processed mRNA transcripts, while structural proteins are translated from incompletely spliced transcripts. Completely spliced transcripts are exported from the nucleus to the cytoplasm by the same mechanism as cellular mRNA. However, Rev is needed to export incompletely spliced mRNAs in order to produce the viral structural proteins.[citation needed]
Rev localization to the nucleus
The arginine-rich domain of the Rev protein, containing a
Binding of Rev to the RRE
The rev response element (RRE) is a 240 base-pair sequence located in the second
Within this purine-rich stem-loop, IIB, are non-canonical base pairs that form as a result of the mRNA stem loop-secondary structure. These base pairs include guanine-adenine (nucleotides 47 and 73, respectively) and guanine-guanine (nucleotides 48–71, respectively). The two base pairs are separated by a non-stacked and bulging uridine that points outwards, away from the ARM-RNA interactions.
The ARM contains residues R35 and R39 that make base-specific contacts with residues on the RRE mRNA, specifically to bases uracil 66, guanine 67, and guanine 70, respectively. On the opposite side of these bases, residues N40 and R44 make base-specific contacts with nucleotides uracil 45, guanine 46, guanine 47, and adenine 73. In addition to these stabilizing contacts, additional Arg residues within the ARM, as well as T34, make nonspecific contacts with bases on the mRNA.[21]
The RRE sequence is cis-acting, and is necessary to achieve high levels of env mRNA in the cytoplasm.[22] The RRE also facilitates multimerization of the Rev proteins, which is required for Rev binding and function.[23] The Rev protein binds unspliced gag and pol transcripts and incompletely spliced env, vif, vpr and vpu transcripts at the RRE, facilitating export to the cytoplasm.[24]
Genomic export from the nucleus
Rev is continuously shuttled between the
Rev-directed export of viral RNAs is similar to the mechanism by which
Regulation of HIV gene expression
Rev acts post-transcriptionally to positively regulate the expression of structural genes and to negatively regulate the expression of
Transition from early to late phase HIV-1 genes
Rev as a target for antiviral therapies
Since Rev is absolutely necessary for HIV-1 replication and it is expressed early on in infection, it has been suggested that Rev is a good target for antiviral therapies.[citation needed]
It has been shown that various organic compounds have the ability to target the Rev/RRE interaction.
Other therapies target the Rev protein itself, since it is an essential component of
Dihydrovaltrate was also identified as a Rev-export inhibitory congener.[citation needed]
References
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