Structure mapping of dengue and Zika viruses reveals functional long-range interactions

Roland G. Huber, Xin Ni Lim, Wy Ching Ng, Adelene Y. L. Sim, Hui Xian Poh, Yang Shen, Su Ying Lim, Karin B. Sundstrom, Xuyang Sun, Jong Ghut Aw, Horng Khit Too, Peng Hee Boey, Andreas Wilm, Tanu Chawla, Milly M. Choy, Lu Jiang, Paola Florez Sessions, Xian Jun Loh, Sylvie Alonso, Martin Hibberd, Niranjan Nagarajan, Eng Eong Ooi, Peter J. Bond (), October M. Sessions () and Yue Wan ()
Additional contact information
Roland G. Huber: Bioinformatics Institute (A*STAR)
Xin Ni Lim: Genome Institute of Singapore
Wy Ching Ng: Duke-NUS Graduate Medical School
Adelene Y. L. Sim: Bioinformatics Institute (A*STAR)
Hui Xian Poh: Genome Institute of Singapore
Yang Shen: Genome Institute of Singapore
Su Ying Lim: Genome Institute of Singapore
Karin B. Sundstrom: Duke-NUS Graduate Medical School
Xuyang Sun: National Neuroscience Institute
Jong Ghut Aw: Genome Institute of Singapore
Horng Khit Too: National University of Singapore
Peng Hee Boey: National University of Singapore
Andreas Wilm: Genome Institute of Singapore
Tanu Chawla: Duke-NUS Graduate Medical School
Milly M. Choy: Genome Institute of Singapore
Lu Jiang: A*STAR
Paola Florez Sessions: Genome Institute of Singapore
Xian Jun Loh: A*STAR
Sylvie Alonso: National University of Singapore
Martin Hibberd: Genome Institute of Singapore
Niranjan Nagarajan: Genome Institute of Singapore
Eng Eong Ooi: Duke-NUS Graduate Medical School
Peter J. Bond: Bioinformatics Institute (A*STAR)
October M. Sessions: Duke-NUS Graduate Medical School
Yue Wan: Genome Institute of Singapore

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Dengue (DENV) and Zika (ZIKV) viruses are clinically important members of the Flaviviridae family with an 11 kb positive strand RNA genome that folds to enable virus function. Here, we perform structure and interaction mapping on four DENV and ZIKV strains inside virions and in infected cells. Comparative analysis of SHAPE reactivities across serotypes nominates potentially functional regions that are highly structured, conserved, and contain low synonymous mutation rates. Interaction mapping by SPLASH identifies many pair-wise interactions, 40% of which form alternative structures, suggesting extensive structural heterogeneity. Analysis of shared interactions between serotypes reveals a conserved macro-organization whereby interactions can be preserved at physical locations beyond sequence identities. We further observe that longer-range interactions are preferentially disrupted inside cells, and show the importance of new interactions in virus fitness. These findings deepen our understanding of Flavivirus genome organization and serve as a resource for designing therapeutics in targeting RNA viruses.

Date: 2019
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DOI: 10.1038/s41467-019-09391-8

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