Pass the Jelly Rolls

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Reza Khayat1 and John E. Johnson1,* 1Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA *Correspondence: [email protected] DOI 10.1016/j.str.2011.06.004

The crystal structure of the vaccinia virus D13 protein presented by Bahar et al. in this issue of Structure displays fused ‘‘virus jelly roll’’ folds, ubiquitous among dsDNA icosahedral viruses. Although D13 is not present in the mature virus, its structure suggests its evolutionary descent from an ancient icosahedral ancestor.

The crystal structure of the D13 protein of virus. They displayed closely similar shell ucts in the icosahedral asymmetric unit, vaccinia virus reported by Bahar et al. forming domains, composed of the jelly displaying undetectable sequence simi- (2011) in this issue of Structure expands roll fold, in spite of their low sequence larity, all had jelly roll folds. The quater- the connectivity among icosahedral and identity. The fold was observed again nary structure of the picornaviruses is now nonicosahedral viruses based on in the third virus structure reported, that strikingly similar to the T = 3 plant virus the ubiquitous ‘‘virus jelly roll’’ tertiary of the satellite tobacco necrosis virus, structures (Figure 1B). The T = 3 capsids fold. The literature describing this fold leading to the apparently correct conclu- have only one type of gene product, now spans more than thirty years and sion that icosahedral ssRNA plant viruses which occupies each of the three quasi- describes its appearance in viruses in- were related through a common ancestor equivalent positions, whereas the picor- fecting all domains of life. Previously, the and retained closely similar tertiary struc- naviruses have different gene products jelly roll fold was only reported in icosahe- tures, despite their broad sequence varia- in the three pseudoequivalent positions. dral capsids, but its role in vaccinia virus, tion. The plot thickened when the T = 1 The picornavirus capsids strongly sug- described in this paper as well as in earlier (pseudo T = 3) structures of human rhino- gested that the gene for the subunit biochemical and electron microscopy virus and poliovirus were determined, and in a T = 3 virus triplicated, and the differ- studies, ties it to other large dsDNA the folds of the three different gene prod- ent genes then evolved independently viruses. Vaccinia virus is among the largest mammalian viruses; it contains over 250 genes and has a brick-shaped morphology with dimensions of 3000 3 2700 3 2500 A˚ in the mature particle. Vaccinia is a close relative of the small pox virus and is the basis for the small pox vaccine. Together with its viral gene product A17, D13 recruits membranes that eventually envelop the virus. Many other structural homologs of D13 play a similar role, in that they are associated with an internal viral membrane of icosahedral particles. D13, however, is only transiently associated with the membranes and is not present in the mature particles. Figure 1. RNA Virus Jelly Rolls The structural biology of icosahedral (A) A diagram of the viral jelly roll tertiary structure observed in many ssRNA icosahedral virus capsids (top right), its topology (lower), and its disposition in a T = 1 icosahedral particle (top left). b strands (represented viral capsid subunits has been rather by yellow or red arrows that correspond to their sheets in the folded structure) and positions of insertions monotonous in terms of their tertiary between strands are shown in the topological representation. The green cylinders represent helices that structures. The viral subunit jelly roll fold are usually conserved. The C–D, E–F, and G–H loops often contain significant insertions. The fold is named after the procedure a baker would use to prepare a jelly roll—i.e., making an extended piece of dough, (Figure 1A) was the only tertiary structure folding it back on itself (as in the topological figure), and then rolling it up as in the tertiary structure figure. observed in icosahedral capsid proteins (B) The relationship between capsids formed by 180 jelly rolls arranged with icosahedral symmetry. (Top) for the first twelve years of virus crystal- A T = 3 capsid (typical of ssRNA plant viruses) formed by one type of gene product. Positions A, B, and C lography (Rossmann and Johnson, 1989). are occupied by subunits with identical amino acid sequences. (Lower left) The picornavirus capsid has three different gene products, all with jelly roll folds, but without a detectable sequence similarity, occu- The first two virus structures determined pying the positions Vp1, Vp2, and Vp3. These are equivalent, in terms of the quaternary structure, to at near atomic resolution were single A, C, and B in the T = 3 virus. (Lower right) The comovirus capsid in which VP2 and VP3 are fused by a linker strand (ss) RNA plant viruses with T = 3 to form a single polypeptide chain made of two jelly rolls. Picorna virus capsids probably evolved from a T = 3 capsid in which the subunit gene triplicated to form three jelly rolls that evolved independently. quasi-symmetry, i.e. the tomato bushy Eventually they were separated by posttranslational proteolysis. The comovirus capsid appears to be stunt virus and the southern bean mosaic an intermediate in this process.

to create very different se- membranes, including the quences with closely similar algal-infecting virus PBCV, folds that reﬂected their origin. the sulfolobus infecting STIV, The addition of a protease, and the PM2 bacteriophage which cleaved the polyprotein (Abrescia et al., 2008; Bam- of capsid subunits, produced ford et al., 2005). the covalently independent The D13 crystal structure proteins constituting the ubiq- now reported here reveals a uitous picornavirus capsid. role for fused jelly rolls that is This hypothesis was sup- related to, but different, from ported by the structure of the those previously observed beanpod mottle virus, a plant (Bahar et al., 2011). The comovirus with a picorna- vaccinia viral gene products virus-like capsid, in which the A17 and D13 recruit the virus ﬁrst two jelly rolls were still membrane that eventually a single polypeptide chain, envelops the mature particle. while the subunit occupying The novel aspect of D13 is the third position was cova- Figure 2. Structure-Based Relationships of dsDNA Virus Jelly Rolls that it is not present in the lently independent. An even Based on structural superpositions, the dsDNA jelly rolls organize as shown. In mature virus but serves as an earlier stage of the evolution each case, the tertiary structure is shown, as well as the quaternary structure of intermediate in the assembly of T = 3 capsids to picorna- the capsids in which they appear. This fold is exceptionally versatile in gener- of the virus membrane and is ating capsids with large pseudoequivalent surface lattices. Both D13 and the virus capsid was found in the adenovirus subunit are associated with viruses infecting mammalian hosts, released from the membrane tobacco ringspot virus, in and they both have elaborate insertions between strands of the jelly rolls prior to particle maturation. whicheachofthethreejelly compared to the other viruses in this category. However, the largest insertion D13 does not interact directly in D13 is in the C terminus jelly roll, while the largest insertions in the adenovirus rolls in the asymmetric unit subunit are in the N-terminal jelly roll. The canonical dsDNA fused jelly rolls are with membranes; rather, it were in a single polypeptide shown for STIV with the strands labeled in the established manner. binds to gene product A17 chain (Lin and Johnson, that resides in the recruited 2003). Thus, the concept of membrane. D13 contributes fused jelly roles was well established in jelly rolls relative to the particle surface is to the crescent-shaped membrane the icosahedral ssRNA virus capsids. different between the dsDNA viruses and morphology that precedes assembly of The structure of the adenovirus hexon the ssRNA viruses. Hexamers or pseudo the particles through the formation hexag- subunit reported by Burnett and col- hexamers in T = 3 and picornavirus virus onal arrays on the outer surface of the leagues (Roberts et al., 1986) revealed capsids have the long dimension of the membranes (Hyunet al., 2007). As the cres- another way in which the jelly roll was jelly rolls approximately tangential to the cents coalesce, a spherical particle enve- incorporated into a virus capsid. Adeno- particle surface, whereas all the dsDNA lope is formed. D13 is released at this stage virus is a 1000A˚ dsDNA virus witha pseudo virus jelly rolls have the long dimension through the action of a virally encoded T = 25 capsid (Figure 2). Its main structural roughly radial relative to the spherical protease, I7, which cleaves A17 at the proteins are 60 identical subunits that particle. Second, the ssRNA fused sub- N-terminal and C-terminal regions (Bisht form the 12 pentamers and 720 identical units appear as ‘‘beads on a string,’’ with et al., 2009). Only the N-terminal cleavage subunits that form 240 pseudo hexamers. discrete jelly rolls linked by an extended is required to release D13, allowing normal The subunits forming pseudo hexamers connector. The fused jelly rolls in the maturation of the particles into the envel- are two jelly rolls that are fused together. dsDNA viruses appear as a single domain oped brick-shaped mature virions. The Trimers of these subunits form a pseudo- with beta sheet that is formed between structure presented by Bahar et al. (2011) hexagonal base, and these hexamers the F strand of the N-terminal jelly roll clearly ties D13 in with the other fused interact with each other to form the pseu- and the B0 strand on the C-terminal jelly double jelly roll structures in terms of doequivalent shell. The outer portion of roll, resulting in a continuous beta sheet tertiary and quaternary structure (Figure 2) the subunit is clearly trimeric, as the that extends through both jelly rolls. and strongly suggests an evolutionary N-terminal jelly roll has two elaborate Fused jelly rolls have appeared in the history for D13 that links it to the estab- insertions between the strands of the subunit structure of the dsDNA PRD1 lished class of dsDNA subunits found in beta sheet, whereas the C-terminal jelly bacteriophage, where they also formed many large dsDNA viruses. has much smaller insertions. trimers that are highly similar to adenovirus Although the fused jelly rolls in the trimers (Bamford et al., 2005). 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