Structure of a Spumaretrovirus Gag Central Domain Reveals an Ancient Retroviral Capsid

Ball, Neil J.; Nicastro, Giuseppe; Dutta, Moumita; Pollard, Dominic J.; Goldstone, David C.; Sanz-Ramos, Marta; Ramos, Andrés; Müllers, Erik; Stirnnagel, Kristin; Stanke, Nicole; Lindemann, Dirk; Stoye, Jonathan P.; Taylor, William R.; Rosenthal, Peter B.; Taylor, Ian A.

doi:10.1371/journal.ppat.1005981

Cited by 20 publications

(26 citation statements)

References 96 publications

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“…These data provide evidence for a structural conservation between orthoretroviral CA and ARC proteins and the weaker alignments observed with orthoretroviral CA-NtDs suggest that orthoretroviral CA-NtDs have undergone much more structural divergence than has occurred in the Ty3 family or ARC proteins. Moreover, these data further support the previously proposed idea that a duplication of a CA-CtD progenitor first gave rise to double domain ancestors and that subsequent divergence of domains resulted in spumaretroviral, orthoretroviral, and Metaviridae-derived proteins such as ARC, that are found presently ( 17, 23 ).…”

Section: Resultssupporting

confidence: 87%

Structure of D. melanogaster ARC1 reveals a repurposed molecule with characteristics of retroviral Gag

Cottee

Letham

Young

et al. 2019

Preprint

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18The tetrapod neuronal protein ARC and its D. melanogaster homologue, dARC1, have 19 important but differing roles in neuronal development. Both are thought to originate 20 through exaptation of ancient Ty3/Gypsy retrotransposon Gag genes, with their novel 21 function relying on an original capacity for self-assembly and encapsidation of nucleic 22 Keywords: ARC; Gag; CA; Neuronal development; TY3/Gypsy. 33 34 lineages of Ty3/Gypsy, since dARC1 clustered with insect Ty3/Gypsy retrotransposons 60 and tetrapod ARCs clustered with fish Ty3/Gypsy retrotransposons (15). 61The relevance of ARC's retrotransposon origin to its function in synaptic plasticity 62 was not immediately obvious until the recent observation that mam-ARC and dARC1 can 63 self-assemble into particles and package RNA for potential transfer between cells (12, 15), 64 similarly to retrotransposons and retroviruses (18, 19). In D. melanogaster, it is proposed 65 that dARC1 expressed at neuromuscular junction presynaptic boutons assembles into 66 particles that encapsidate dARC1 mRNA. Loaded particles might then be packaged and 67 released as extracellular vesicles for intercellular transfer to the post synapse where 68 mRNA release and translation can take place (12, 15), Similarly, mam-ARC can also 69 encapsidate ARC mRNA into particles, allowing transfer from donor to recipient neurons, 70where ARC mRNA can be translated (15). 71Since both dARC1 and mam-ARC are able to form capsid-like particles (12, 15), it 72 seems likely that they share a degree of structurally similarity. To date, crystal structures of 73 the individual domains from rARC have been determined (16) along with the solution NMR 74 structure of the rARC CA (20). Here we report two crystal structures of the entire CA 75 region of dARC1 at 1.7 Å and 2.3 Å and consider these structures in comparison to those 76 of rARC and retroviral CA. dARC1 comprises two α-helical domains with a fold related to 77 that observed in the CA-NtD and CA-CtD of orthoretroviral and spumaretroviral CA. 78However, we observe significant divergence in the NtD of dARC1 where an extended 79 hydrophobic strand that packs against α1 and α3 of the core fold replaces the N-terminal 80 β-hairpin and helix α1 found in orthoretroviral CAs. In the rARC structure, this hydrophobic 81 strand is replaced by peptides from the binding partners Ca 2+ /calmodulin-dependent 82 protein kinase 2A (CamK2A) and transmembrane AMPAR regulatory protein γ2 (TARPγ2) 83 and may represent a functional adaptation for the recruitment of partner proteins. We also 84show that dARC1 utilises the same CtD-CtD interface required for assembly of retroviral 85 7 CA into mature particles and propose that this obligate dimer represents a building block 86 for dARC1 particle assembly. Further examination of the relationship between dARC1, 87 mam-ARC and Gag from Ty retrotransposon families, reveals that, although dARC1 and 88 mam-ARC are functional orthologues, the structural divergence in dARC1 and mam-ARC 89 CA domains is consistent with the noti...

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Section: Resultssupporting

confidence: 87%

Structure of D. melanogaster ARC1 reveals a repurposed molecule with characteristics of retroviral Gag

Cottee

Letham

Young

et al. 2019

Preprint

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“…On the basis of these structural comparisons, and a variety of recently described functional assays [5], we can conclude that the central region of the spumavirus gag gene encodes a polypeptide sequence related to that of the corresponding region of orthoretroviral, CA. It therefore seems reasonable to suppose that the last common ancestor of orthoretroviruses and spumaviruses possessed such a sequence.…”

Section: Discussionmentioning

confidence: 82%

“…), and the new structure of the foamy virus capsid [5] (PDB codes: 5m1g, 5m1h), the foamy virus structure was compared to one of the few full double domain ortho virus structures, the HIV capsid with PDB code: 3nte, using the flexible superposition program SAP [6]. Even though this program has a tolerant approach to relative domain shifts, the comparison produced a high RMSD value of 14Å over the 100 best superposed positions.…”

Section: Resultsmentioning

confidence: 99%

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A comparative analysis of the foamy and ortho virus capsid structures reveals an ancient domain duplication

2017

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BackgroundThe Spumaretrovirinae (foamy viruses) and the Orthoretrovirinae (e.g. HIV) share many similarities both in genome structure and the sequences of the core viral encoded proteins, such as the aspartyl protease and reverse transcriptase. Similarity in the gag region of the genome is less obvious at the sequence level but has been illuminated by the recent solution of the foamy virus capsid (CA) structure. This revealed a clear structural similarity to the orthoretrovirus capsids but with marked differences that left uncertainty in the relationship between the two domains that comprise the structure.MethodsWe have applied protein structure comparison methods in order to try and resolve this ambiguous relationship. These included both the DALI method and the SAP method, with rigorous statistical tests applied to the results of both methods. For this, we employed collections of artificial fold ’decoys’ (generated from the pair of native structures being compared) to provide a customised background distribution for each comparison, thus allowing significance levels to be estimated.ResultsWe have shown that the relationship of the two domains conforms to a simple linear correspondence rather than a domain transposition. These similarities suggest that the origin of both viral capsids was a common ancestor with a double domain structure. In addition, we show that there is also a significant structural similarity between the amino and carboxy domains in both the foamy and ortho viruses.ConclusionsThese results indicate that, as well as the duplication of the double domain capsid, there may have been an even more ancient gene-duplication that preceded the double domain structure. In addition, our structure comparison methodology demonstrates a general approach to problems where the components have a high intrinsic level of similarity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12900-017-0073-0) contains supplementary material, which is available to authorized users.

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“…1 and 2). Importantly, nonpolar residues, which stabilize the hydrophobic core of the ␣-helical bundles of both the CA NTD and CA CTD (10,19), are conserved in all CP/CA proteins. Thus, patterns of sequence and secondary structure conservation strongly support the homology of the CA/ CP-NC module of all reverse-transcribing viruses except hepadnaviruses.…”

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confidence: 99%

Homologous Capsid Proteins Testify to the Common Ancestry of Retroviruses, Caulimoviruses, Pseudoviruses, and Metaviruses

Krupovìč

Koonin

2017

J Virol

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Structure of a Spumaretrovirus Gag Central Domain Reveals an Ancient Retroviral Capsid

Cited by 20 publications

References 96 publications

Structure of D. melanogaster ARC1 reveals a repurposed molecule with characteristics of retroviral Gag

Structure of D. melanogaster ARC1 reveals a repurposed molecule with characteristics of retroviral Gag

A comparative analysis of the foamy and ortho virus capsid structures reveals an ancient domain duplication

Homologous Capsid Proteins Testify to the Common Ancestry of Retroviruses, Caulimoviruses, Pseudoviruses, and Metaviruses

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