In vitro functional analysis of gRNA sites regulating assembly of hepatitis B virus

Patel, Nikesh; Clark, Sam; Weiß, Eva U.; Mata, Carlos P.; Bohon, Jen; Farquhar, Erik R.; Maskell, Daniel P.; Ranson, Neil A.; Twarock, Reidun; Stockley, Peter G.

doi:10.1038/s42003-021-02897-2

Title: In vitro functional analysis of gRNA sites regulating assembly of hepatitis B virus

Journal Article · Thu Dec 16 00:00:00 EST 2021 · Communications Biology

DOI:https://doi.org/10.1038/s42003-021-02897-2· OSTI ID:1875647

^[1];

^[2]; Weiß, Eva U. ^[3]; Mata, Carlos P. ^[4];

^[5];

^[6]; Maskell, Daniel P. ^[1];

^[1]; Twarock, Reidun ^[2];

^[1]

Univ. of Leeds (United Kingdom)
Univ. of York (United Kingdom)
Univ. of Würzburg (Germany); Univ. of York (United Kingdom)
National Centre for Microbiology (ISCIII). Majadahonda, Madrid (Spain); Univ. of Leeds (United Kingdom)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Brookhaven National Lab. (BNL), Upton, NY (United States)
Brookhaven National Lab. (BNL), Upton, NY (United States)

The roles of RNA sequence/structure motifs, Packaging Signals (PSs), for regulating assembly of an HBV genome transcript have been investigated in an efficient in vitro assay containing only core protein (Cp) and RNA. Variants of three conserved PSs, within the genome of a strain not used previously, preventing correct presentation of a Cp-recognition loop motif are differentially deleterious for assembly of nucleocapsid-like particles (NCPs). Cryo-electron microscopy reconstruction of the T = 4 NCPs formed with the wild-type gRNA transcript, reveal that the interior of the Cp shell is in contact with lower resolution density, potentially encompassing the arginine-rich protein domains and gRNA. Symmetry relaxation followed by asymmetric reconstruction reveal that such contacts are made at every symmetry axis. We infer from their regulation of assembly that some of these contacts would involve gRNA PSs, and confirmed this by X-ray RNA footprinting. Mutation of the ε stem-loop in the gRNA, where polymerase binds in vivo, produces a poor RNA assembly substrate with Cp alone, largely due to alterations in its conformation. The results show that RNA PSs regulate assembly of HBV genomic transcripts in vitro, and therefore may play similar roles in vivo, in concert with other molecular factors.

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Research Organization:: Brookhaven National Lab. (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: SC0012704; P30-EB-009998; 1228549

OSTI ID:: 1875647

Report Number(s):: BNL-223145-2022-JACI

Journal Information:: Communications Biology, Vol. 4, Issue 1; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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