Structure of HIV-1 RRE stem-loop II identifies two conformational states of the high-affinity Rev binding site

Tipo, Jerricho; Gottipati, Keerthi; Slaton, Michael; Gonzalez-Gutierrez, Giovanni; Choi, Kyung H.

doi:10.1038/s41467-024-48162-y

Title: Structure of HIV-1 RRE stem-loop II identifies two conformational states of the high-affinity Rev binding site

Journal Article · 17 May 2024 · Nature Communications

DOI: https://doi.org/10.1038/s41467-024-48162-y · OSTI ID:2471059

^[1];

^[2]; Slaton, Michael ^[2];

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The University of Texas Medical Branch, Galveston, TX (United States); Indiana University, Bloomington, IN (United States)
Indiana University, Bloomington, IN (United States)

During HIV infection, specific RNA-protein interaction between the Rev response element (RRE) and viral Rev protein is required for nuclear export of intron-containing viral mRNA transcripts. Rev initially binds the high-affinity site in stem-loop II, which promotes oligomerization of additional Rev proteins on RRE. Here, we present the crystal structure of RRE stem-loop II in distinct closed and open conformations. The high-affinity Rev-binding site is located within the three-way junction rather than the predicted stem IIB. The closed and open conformers differ in their non-canonical interactions within the three-way junction, and only the open conformation has the widened major groove conducive to initial Rev interaction. Rev binding assays show that RRE stem-loop II has high- and low-affinity binding sites, each of which binds a Rev dimer. We propose a binding model, wherein Rev-binding sites on RRE are sequentially created through structural rearrangements induced by Rev-RRE interactions.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); National Institutes of Health (NIH); Michigan Economic Development Corporation; Michigan Technology Tri-Corridor

Grant/Contract Number:: AC02-05CH11231; AC02-06CH11357

OSTI ID:: 2471059

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 15; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (71)

UCSF Chimera?A visualization system for exploratory research and analysis Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Journal of Computational Chemistry, Vol. 25, Issue 13 https://doi.org/10.1002/jcc.20084	journal	January 2004
Cooperative dimerization of a stably folded protein directed by a flexible RNA in the assembly of the HIV Rev dimer-RRE stem II complex Tanamura, Satoshi; Terakado, Hiroto; Harada, Kazuo Journal of Molecular Recognition, Vol. 29, Issue 5 https://doi.org/10.1002/jmr.2518	journal	December 2015
A Molecular Rheostat Mann, Derek A.; Mikaélian, Ivan; Zemmel, Rodney W. Journal of Molecular Biology, Vol. 241, Issue 2 https://doi.org/10.1006/jmbi.1994.1488	journal	August 1994
Flexible Regions of RNA Structure Facilitate Co-operative Rev Assembly on the Rev-response Element Zemmel, Rodney W.; Kelley, Ann C.; Karn, Jonathan Journal of Molecular Biology, Vol. 258, Issue 5 https://doi.org/10.1006/jmbi.1996.0285	journal	May 1996
The structure of the HIV-1 RRE high affinity rev binding site at 1.6 Å resolution Ippolito, Joseph A.; Steitz, Thomas A. Journal of Molecular Biology, Vol. 295, Issue 4 https://doi.org/10.1006/jmbi.1999.3405	journal	January 2000
Sequence Requirements for Rev Multimerization in Vivo Madore, Steven J.; Tiley, Laurence S.; Malim, Michael H. Virology, Vol. 202, Issue 1 https://doi.org/10.1006/viro.1994.1334	journal	July 1994
HIV-1 Tat protein increases transcriptional initiation and stabilizes elongation Laspia, Michael F.; Rice, Andrew P.; Mathews, Michael B. Cell, Vol. 59, Issue 2 https://doi.org/10.1016/0092-8674(89)90290-0	journal	October 1989
Functional dissection of the HIV-1 Rev trans-activator—Derivation of a trans-dominant repressor of Rev function Malim, Michael H.; Böhnlein, Sabine; Hauber, Joachim Cell, Vol. 58, Issue 1 https://doi.org/10.1016/0092-8674(89)90416-9	journal	July 1989
HIV-1 Tat protein trans-activates transcription in vitro Marciniak, Robert A.; Calnan, Barbara J.; Frankel, Alan D. Cell, Vol. 63, Issue 4 https://doi.org/10.1016/0092-8674(90)90145-5	journal	November 1990
HIV-1 structural gene expression requires the binding of multiple Rev monomers to the viral RRE: Implications for HIV-1 latency Malim, Michael H.; Cullen, Bryan R. Cell, Vol. 65, Issue 2 https://doi.org/10.1016/0092-8674(91)90158-U	journal	April 1991
HIV-1 rev regulation involves recognition of non-Watson-Crick base pairs in viral RNA Bartel, David P.; Zapp, Maria L.; Green, Michael R. Cell, Vol. 67, Issue 3 https://doi.org/10.1016/0092-8674(91)90527-6	journal	November 1991
RNA recognition by an isolated α helix Tan, Ruoying; Chen, Lily; Buettner, Joseph A. Cell, Vol. 73, Issue 5 https://doi.org/10.1016/0092-8674(93)90280-4	journal	June 1993
The HIV-1 Rev Activation Domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs Fischer, Utz; Huber, Jochen; Boelens, Wilbert C. Cell, Vol. 82, Issue 3 https://doi.org/10.1016/0092-8674(95)90436-0	journal	August 1995
CRM1 Is an Export Receptor for Leucine-Rich Nuclear Export Signals Fornerod, Maarten; Ohno, Mutsuhito; Yoshida, Minoru Cell, Vol. 90, Issue 6 https://doi.org/10.1016/S0092-8674(00)80371-2	journal	September 1997
The importin-beta family member Crm1p bridges the interaction between Rev and the nuclear pore complex during nuclear export Neville, Megan; Stutz, Francoise; Lee, Linda Current Biology, Vol. 7, Issue 10 https://doi.org/10.1016/S0960-9822(06)00335-6	journal	October 1997
Structural Model for the Cooperative Assembly of HIV-1 Rev Multimers on the RRE as Deduced from Analysis of Assembly-Defective Mutants Jain, Chaitanya; Belasco, Joel G. Molecular Cell, Vol. 7, Issue 3 https://doi.org/10.1016/S1097-2765(01)00207-6	journal	March 2001
An Unusual Topological Structure of the HIV-1 Rev Response Element Fang, Xianyang; Wang, Jinbu; O’Carroll, Ina P. Cell, Vol. 155, Issue 3 https://doi.org/10.1016/j.cell.2013.10.008	journal	October 2013
A DEAD-Box Helicase Mediates an RNA Structural Transition in the HIV-1 Rev Response Element Hammond, John A.; Lamichhane, Rajan; Millar, David P. Journal of Molecular Biology, Vol. 429, Issue 5 https://doi.org/10.1016/j.jmb.2017.01.018	journal	March 2017
A new HIV-1 Rev structure optimizes interaction with target RNA (RRE) for nuclear export Watts, Norman R.; Eren, Elif; Zhuang, Xiaolei Journal of Structural Biology, Vol. 203, Issue 2 https://doi.org/10.1016/j.jsb.2018.03.011	journal	August 2018
A Solution to Limited Genomic Capacity: Using Adaptable Binding Surfaces to Assemble the Functional HIV Rev Oligomer on RNA Daugherty, Matthew D.; D'Orso, Iván; Frankel, Alan D. Molecular Cell, Vol. 31, Issue 6 https://doi.org/10.1016/j.molcel.2008.07.016	journal	September 2008
Biochemical characterization of binding of multiple HIV-1 Rev monomeric proteins to the Rev responsive element Daly, Thomas J.; Doten, Reed C.; Rennert, Paul Biochemistry, Vol. 32, Issue 39 https://doi.org/10.1021/bi00090a028	journal	October 1993
The HIV-1 rev trans-activator acts through a structured target sequence to activate nuclear export of unspliced viral mRNA Malim, Michael H.; Hauber, Joachim; Le, Shu-Yun Nature, Vol. 338, Issue 6212 https://doi.org/10.1038/338254a0	journal	March 1989
Sequence-specific RNA binding by the HIV-1 Rev protein Zapp, Maria L.; Green, Michael R. Nature, Vol. 342, Issue 6250 https://doi.org/10.1038/342714a0	journal	December 1989
Specific binding of HIV-1 recombinant Rev protein to the Rev-responsive element in vitro Daly, Thomas J.; Cook, Kathleen Sue; Gray, Gary S. Nature, Vol. 342, Issue 6251 https://doi.org/10.1038/342816a0	journal	December 1989
Architecture and secondary structure of an entire HIV-1 RNA genome Watts, Joseph M.; Dang, Kristen K.; Gorelick, Robert J. Nature, Vol. 460, Issue 7256 https://doi.org/10.1038/nature08237	journal	August 2009
Association of Viral Reverse Transcriptase with an Enzyme degrading the RNA Moiety of RNA-DNA Hybrids MÖLling, K.; Bolognesi, D. P.; Bauer, H. Nature New Biology, Vol. 234, Issue 51 https://doi.org/10.1038/newbio234240a0	journal	December 1971
Recombinant RNA technology: the tRNA scaffold Ponchon, Luc; Dardel, Frédéric Nature Methods, Vol. 4, Issue 7 https://doi.org/10.1038/nmeth1058	journal	June 2007
Deep penetration of an α-helix into a widened RNA major groove in the HIV-1 rev peptide–RNA aptamer complex Ye, Xiaomei; Gorin, Andrey; Ellington, Andrew D. Nature Structural Biology, Vol. 3, Issue 12 https://doi.org/10.1038/nsb1296-1026	journal	December 1996
Structural insights into the Cyclin T1–Tat–TAR RNA transcription activation complex from EIAV Anand, Kanchan; Schulte, Antje; Vogel-Bachmayr, Karin Nature Structural & Molecular Biology, Vol. 15, Issue 12 https://doi.org/10.1038/nsmb.1513	journal	November 2008
Structural basis for cooperative RNA binding and export complex assembly by HIV Rev Daugherty, Matthew D.; Liu, Bella; Frankel, Alan D. Nature Structural & Molecular Biology, Vol. 17, Issue 11 https://doi.org/10.1038/nsmb.1902	journal	October 2010
Native mass spectrometry reveals the initial binding events of HIV-1 rev to RRE stem II RNA Schneeberger, Eva-Maria; Halper, Matthias; Palasser, Michael Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-19144-7	journal	November 2020
Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase Lee, Eunhye; Bujalowski, Paul J.; Teramoto, Tadahisa Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-22846-1	journal	May 2021
A mutation in T7 RNA polymerase that facilitates promoter clearance Guillerez, J.; Lopez, P. J.; Proux, F. Proceedings of the National Academy of Sciences, Vol. 102, Issue 17 https://doi.org/10.1073/pnas.0407141102	journal	April 2005
Resistance to RevM10 inhibition reflects a conformational switch in the HIV-1 Rev response element Legiewicz, M.; Badorrek, C. S.; Turner, K. B. Proceedings of the National Academy of Sciences, Vol. 105, Issue 38 https://doi.org/10.1073/pnas.0804461105	journal	September 2008
The crystal structure of the Rev binding element of HIV-1 reveals novel base pairing and conformational variability Hung, Li-Wei; Holbrook, Elizabeth L.; Holbrook, Stephen R. Proceedings of the National Academy of Sciences, Vol. 97, Issue 10 https://doi.org/10.1073/pnas.090588197	journal	May 2000
HIV Rev response element (RRE) directs assembly of the Rev homooligomer into discrete asymmetric complexes Daugherty, Matthew D.; Booth, David S.; Jayaraman, Bhargavi Proceedings of the National Academy of Sciences, Vol. 107, Issue 28 https://doi.org/10.1073/pnas.1007022107	journal	June 2010
Human immunodeficiency virus type 1 regulator of virion expression, rev, forms nucleoprotein filaments after binding to a purine-rich "bubble" located within the rev-responsive region of viral mRNAs. Heaphy, S.; Finch, J. T.; Gait, M. J. Proceedings of the National Academy of Sciences, Vol. 88, Issue 16 https://doi.org/10.1073/pnas.88.16.7366	journal	August 1991
Oligomerization and RNA binding domains of the type 1 human immunodeficiency virus Rev protein: a dual function for an arginine-rich binding motif. Zapp, M. L.; Hope, T. J.; Parslow, T. G. Proceedings of the National Academy of Sciences, Vol. 88, Issue 17 https://doi.org/10.1073/pnas.88.17.7734	journal	September 1991
The role of Tat in the human immunodeficiency virus life cycle indicates a primary effect on transcriptional elongation. Feinberg, M. B.; Baltimore, D.; Frankel, A. D. Proceedings of the National Academy of Sciences, Vol. 88, Issue 9 https://doi.org/10.1073/pnas.88.9.4045	journal	May 1991
Identification of a high-affinity RNA-binding site for the human immunodeficiency virus type 1 Rev protein. Tiley, L. S.; Malim, M. H.; Tewary, H. K. Proceedings of the National Academy of Sciences, Vol. 89, Issue 2 https://doi.org/10.1073/pnas.89.2.758	journal	January 1992
The Specificity of the CRM1-Rev Nuclear Export Signal Interaction Is Mediated by RanGTP Askjaer, Peter; Jensen, Torben Heick; Nilsson, Jakob Journal of Biological Chemistry, Vol. 273, Issue 50 https://doi.org/10.1074/jbc.273.50.33414	journal	December 1998
Localization of HIV-1 RNA in mammalian nuclei. Zhang, G.; Zapp, M. L.; Yan, G. The Journal of cell biology, Vol. 135, Issue 1 https://doi.org/10.1083/jcb.135.1.9	journal	October 1996
Rev–RRE Functional Activity Differs Substantially Among Primary HIV-1 Isolates Jackson, Patrick E.; Tebit, Denis M.; Rekosh, David AIDS Research and Human Retroviruses, Vol. 32, Issue 9 https://doi.org/10.1089/aid.2016.0047	journal	September 2016
Forna (force-directed RNA): Simple and effective online RNA secondary structure diagrams Kerpedjiev, Peter; Hammer, Stefan; Hofacker, Ivo L. Bioinformatics, Vol. 31, Issue 20 https://doi.org/10.1093/bioinformatics/btv372	journal	June 2015
Sequence specificity of viral end DNA binding by HIV-1 integrase reveals critical regions for protein-DNA interaction Esposito, D. The EMBO Journal, Vol. 17, Issue 19 https://doi.org/10.1093/emboj/17.19.5832	journal	October 1998
Oligoribonucleotide synthesis using T7 RNA polymerase and synthetic DNA templates Milligan, John F.; Groebe, Duncan R.; Witherell, Gary W. Nucleic Acids Research, Vol. 15, Issue 21 https://doi.org/10.1093/nar/15.21.8783	journal	January 1987
Characterization of HIV-1 REV protein: binding stoichiometry and minimal RNA substrate Cook, Kathleen Sue; Fisk, Gregory J.; Hauber, Joachim Nucleic Acids Research, Vol. 19, Issue 7 https://doi.org/10.1093/nar/19.7.1577	journal	January 1991
Structural basis for cloverleaf RNA-initiated viral genome replication Gottipati, Keerthi; McNeme, Sean C.; Tipo, Jerricho Nucleic Acids Research, Vol. 51, Issue 16 https://doi.org/10.1093/nar/gkad618	journal	July 2023
A DEAD-box protein acts through RNA to promote HIV-1 Rev-RRE assembly Lamichhane, Rajan; Hammond, John A.; Pauszek, Raymond F. Nucleic Acids Research, Vol. 45, Issue 8 https://doi.org/10.1093/nar/gkx206	journal	March 2017
Transcriptional and Posttranscriptional Regulation of HIV-1 Gene Expression Karn, J.; Stoltzfus, C. M. Cold Spring Harbor Perspectives in Medicine, Vol. 2, Issue 2 https://doi.org/10.1101/cshperspect.a006916	journal	November 2011
Towards rationalization of crystallization screening for small- to medium-sized academic laboratories: the PACT/JCSG+ strategy Newman, Janet; Egan, David; Walter, Thomas S. Acta Crystallographica Section D Biological Crystallography, Vol. 61, Issue 10 https://doi.org/10.1107/S0907444905024984	journal	September 2005
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix Liebschner, Dorothee; Afonine, Pavel V.; Baker, Matthew L. Acta Crystallographica Section D Structural Biology, Vol. 75, Issue 10 https://doi.org/10.1107/S2059798319011471	journal	October 2019
alpha Helix-RNA Major Groove Recognition in an HIV-1 Rev Peptide-RRE RNA Complex Battiste, J. L.; Mao, H.; Rao, N. S. Science, Vol. 273, Issue 5281 https://doi.org/10.1126/science.273.5281.1547	journal	September 1996
Limited Nucleotide Changes in the Rev Response Element (RRE) during HIV-1 Infection Alter Overall Rev-RRE Activity and Rev Multimerization Sloan, Emily A.; Kearney, Mary F.; Gray, Laurie R. Journal of Virology, Vol. 87, Issue 20 https://doi.org/10.1128/JVI.01392-13	journal	October 2013
Kinetic and Molecular Analysis of Nuclear Export Factor CRM1 Association with Its Cargo In Vivo Daelemans, Dirk; Costes, Sylvain V.; Lockett, Stephen Molecular and Cellular Biology, Vol. 25, Issue 2 https://doi.org/10.1128/MCB.25.2.728-739.2005	journal	January 2005
Regulation of human immunodeficiency virus env expression by the rev gene product Hammarskjöld, M. L.; Heimer, J.; Hammarskjöld, B. Journal of Virology, Vol. 63, Issue 5 https://doi.org/10.1128/jvi.63.5.1959-1966.1989	journal	May 1989
Functional mapping of the human immunodeficiency virus type 1 Rev RNA binding domain: new insights into the domain structure of Rev and Rex Böhnlein, E.; Berger, J.; Hauber, J. Journal of Virology, Vol. 65, Issue 12 https://doi.org/10.1128/jvi.65.12.7051-7055.1991	journal	December 1991
A specific sequence with a bulged guanosine residue(s) in a stem-bulge-stem structure of Rev-responsive element RNA is required for trans activation by human immunodeficiency virus type 1 Rev Holland, S. M.; Chavez, M.; Gerstberger, S. Journal of Virology, Vol. 66, Issue 6 https://doi.org/10.1128/jvi.66.6.3699-3706.1992	journal	June 1992
Alternative splicing of human immunodeficiency virus type 1 mRNA modulates viral protein expression, replication, and infectivity. Purcell, D. F.; Martin, M. A. Journal of Virology, Vol. 67, Issue 11 https://doi.org/10.1128/jvi.67.11.6365-6378.1993	journal	January 1993
Dominant negative mutants of human T-cell leukemia virus type I Rex and human immunodeficiency virus type 1 Rev fail to multimerize in vivo Bogerd, H.; Greene, W. C. Journal of Virology, Vol. 67, Issue 5 https://doi.org/10.1128/jvi.67.5.2496-2502.1993	journal	May 1993
The basic domain of Rev from human immunodeficiency virus type 1 specifically blocks the entry of U4/U6.U5 small nuclear ribonucleoprotein in spliceosome assembly Kjems, J.; Sharp, P. A. Journal of Virology, Vol. 67, Issue 8 https://doi.org/10.1128/jvi.67.8.4769-4776.1993	journal	August 1993
HIV-1: Fifteen Proteins and an RNA Frankel, Alan D.; Young, John A. T. Annual Review of Biochemistry, Vol. 67, Issue 1 https://doi.org/10.1146/annurev.biochem.67.1.1	journal	June 1998
The Hiv-1 rev Protein Pollard, Victoria W.; Malim, Michael H. Annual Review of Microbiology, Vol. 52, Issue 1 https://doi.org/10.1146/annurev.micro.52.1.491	journal	October 1998
Noncanonical G(syn)-G(anti) base pairs stabilized by sulphate anions in two X-ray structures of the (GUGGUCUGAUGAGGCC) RNA duplex Rypniewski, W.; Adamiak, D. A.; Milecki, J. RNA, Vol. 14, Issue 9 https://doi.org/10.1261/rna.1164308	journal	July 2008
Topology of three-way junctions in folded RNAs Lescoute, A. RNA, Vol. 12, Issue 1 https://doi.org/10.1261/rna.2208106	journal	January 2006
Prevalence of syn nucleobases in the active sites of functional RNAs Sokoloski, J. E.; Godfrey, S. A.; Dombrowski, S. E. RNA, Vol. 17, Issue 10 https://doi.org/10.1261/rna.2759911	journal	August 2011
HIV Rev Assembly on the Rev Response Element (RRE): A Structural Perspective Rausch, Jason; Grice, Stuart Viruses, Vol. 7, Issue 6 https://doi.org/10.3390/v7062760	journal	June 2015
RNA-guided assembly of Rev-RRE nuclear export complexes Bai, Yun; Tambe, Akshay; Zhou, Kaihong eLife, Vol. 3 https://doi.org/10.7554/eLife.03656	journal	August 2014
RNA-directed remodeling of the HIV-1 protein Rev orchestrates assembly of the Rev–Rev response element complex Jayaraman, Bhargavi; Crosby, David C.; Homer, Christina eLife, Vol. 3 https://doi.org/10.7554/eLife.04120	journal	December 2014
The export receptor Crm1 forms a dimer to promote nuclear export of HIV RNA Booth, David S.; Cheng, Yifan; Frankel, Alan D. eLife, Vol. 3 https://doi.org/10.7554/eLife.04121	journal	December 2014

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60 APPLIED LIFE SCIENCES
RNA
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X-ray crystallography

Title: Structure of HIV-1 RRE stem-loop II identifies two conformational states of the high-affinity Rev binding site

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