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Dryad

Data for: A structure-based mechanism for displacement of the HEXIM adapter from 7SK small nuclear RNA

Abstract

Productive transcriptional elongation of many cellular and viral mRNAs requires transcriptional factors to extract pTEFb from the 7SK snRNP by modulating the association between the HEXIM protein and the 7SK snRNA.  Here we report the structure of the HEXIM arginine-rich motif in complex with the apical stemloop-1 of 7SK (7SK-SL1apical) and detail how the HIV transcriptional regulator Tat from various subtypes overcome the structural constraints required to displace HEXIM. While most interactions between 7SK and HEXIM and Tat are similar, critical differences exist that guide function. First, the conformational plasticity of 7SK enables the formation of three different base pair configurations at a critical remodeling site, which allows for the modulation required for HEXIM binding and its subsequent displacement by Tat. Furthermore, the specific sequence variations observed in various Tat subtypes all converge on remodeling 7SK at this region. Second, we show that HEXIM primes its own displacement by causing specific local destabilization upon binding a feature that is then exploited by Tat to bind 7SK more efficiently. Overall, our study details the molecular environment presented by HEXIM and uncovers a destabilization-driven displacement strategy that increases the conformational sampling of 7SK-snRNP, which may allow diverse transcriptional factors to competitively regulate pTEFb.