Switch from capsid protein import to adenovirus assembly by cleavage of nuclear transport signals

Wodrich, Harald; Guan, Tinglu; Cingolani, Gino; Seggern, D von; Nemerow, Glen R.; Gerace, Larry

doi:10.1093/emboj/cdg614

Cited by 79 publications

(110 citation statements)

References 85 publications

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“…The current model has protein VI residing at partial occupancy (and therefore poorly resolved by cryoEM) within the central cavities, beneath each of the hexon trimers [Saban et al, 2006]. Residence at this position agrees well with its function as a nuclear import shuttle and with biochemical data mapping the protein VI-interacting hexon residues to this cavity [Wodrich et al, 2003]. Apparently protein VI is masked underneath the hexons until low pH from endosomal acidification triggers the release of vertex components (fiber, penton base, IIIa, and peripentonal hexons), exposing some protein VI and allowing it to lyse the endosomal membrane [Wiethoff et al, 2005].…”

Section: Minor Capsid Proteinssupporting

confidence: 64%

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Current Advances and Future Challenges in Adenoviral Vector Biology and Targeting

Campos¹,

Barry²

2007

CGT

170

122

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Gene delivery vectors based on Adenoviral (Ad) vectors have enormous potential for the treatment of both hereditary and acquired disease. Detailed structural analysis of the Ad virion, combined with functional studies has broadened our knowledge of the structure/function relationships between Ad vectors and host cells/tissues and substantial achievement has been made towards a thorough understanding of the biology of Ad vectors. The widespread use of Ad vectors for clinical gene therapy is compromised by their inherent immunogenicity. The generation of safer and more effective Ad vectors, targeted to the site of disease, has therefore become a great ambition in the field of Ad vector development. This review provides a synopsis of the structure/function relationships between Ad vectors and host systems and summarizes the many innovative approaches towards achieving Ad vector targeting.

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Section: Minor Capsid Proteinssupporting

confidence: 64%

“…Immature protein VI also functions as a nuclear shuttle to bind and import hexon trimers into the nucleus during particle assembly [Wodrich et al, 2003]. Protein VI was originally localized to regions underneath and between the five peripentonal hexon trimers and the penton base at each vertex.…”

Section: Minor Capsid Proteinsmentioning

confidence: 99%

Current Advances and Future Challenges in Adenoviral Vector Biology and Targeting

Campos¹,

Barry²

2007

CGT

170

122

View full text Add to dashboard Cite

show abstract

“…In the third place, the immature adenovirus core is a tightly compacted sphere that remains bound to capsid fragments even in high stress conditions. Notably, precursor protein pVI, located at the inner surface the icosahedral shell, binds both hexon and DNA (56,57). All these observations indicate that the interactions established by precursor proteins, whether in the capsid or between capsid and core (e.g.…”

Section: Discussionmentioning

confidence: 91%

The Role of Capsid Maturation on Adenovirus Priming for Sequential Uncoating

Pérez-Berná

Ortega-Esteban

Menéndez-Conejero

et al. 2012

Journal of Biological Chemistry

132

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“…Here we report to our knowledge the first structure of protein VI, which plays multiple roles in the adenovirus life cycle-it functions as a cofactor for the adenovirus protease (AVP) and as a chaperone for nuclear transport, and is essential for virus assembly and endosome lysis (26)(27)(28)(29)(30). One copy of protein VI is found intimately associated with the base of each PPH on the capsid interior.…”

Section: Resultsmentioning

confidence: 99%

Structures and organization of adenovirus cement proteins provide insights into the role of capsid maturation in virus entry and infection

Reddy¹,

Nemerow

2014

Proc. Natl. Acad. Sci. U.S.A.

118

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Adenovirus cement proteins play crucial roles in virion assembly, disassembly, cell entry, and infection. Based on a refined crystal structure of the adenovirus virion at 3.8-Å resolution, we have determined the structures of all of the cement proteins (IIIa, VI, VIII, and IX) and their organization in two distinct layers. We have significantly revised the recent cryoelectron microscopy models for proteins IIIa and IX and show that both are located on the capsid exterior. Together, the cement proteins exclusively stabilize the hexon shell, thus rendering penton vertices the weakest links of the adenovirus capsid. We describe, for the first time to our knowledge, the structure of protein VI, a key membrane-lytic molecule, and unveil its associations with VIII and core protein V, which together glue peripentonal hexons beneath the vertex region and connect them to the rest of the capsid on the interior. Following virion maturation, the cleaved N-terminal propeptide of VI is observed, reaching deep into the peripentonal hexon cavity, detached from the membrane-lytic domain, so that the latter can be released. Our results thus provide the molecular basis for the requirement of maturation cleavage of protein VI. This process is essential for untethering and release of the membrane-lytic region, which is known to mediate endosome rupture and delivery of partially disassembled virions into the host cell cytoplasm.human adenovirus | cement protein scaffold | structure-function relationships H uman adenoviruses (HAdVs) are large (∼150 nm in diameter, 150-MDa) nonenveloped double-stranded DNA (dsDNA) viruses that cause respiratory, ocular, and enteric diseases (1). Although these diseases are self-limiting in immunocompetent individuals, they cause significant morbidity in AIDS, cancer, and organ transplant patients with compromised immune systems (2-4). Because of their broad cell tropism and ease of genome manipulation, replication-deficient or conditionally replicating HAdVs are also being evaluated in the clinic as potential vaccine and gene therapy vectors (5).The capsid shell of an adenovirus (Ad) comprises multiple copies of three major capsid proteins (MCPs; hexon, penton base, and fiber) and four minor/cement proteins (IIIa, VI, VIII, and IX) that are organized with pseudo-T = 25 icosahedral symmetry ( Fig. 1 A and B). In addition, six other proteins (V, VII, μ, IVa2, terminal protein, and adenovirus protease) are encapsidated along with the 36-kb dsDNA genome inside the capsid (Fig. 1A). The crystal structures of all three MCPs are known, and so is their organization in the capsid from prior X-ray crystallography (6-8) and cryoelectron microscopy (cryo-EM) analyses (9, 10). Recently, high-resolution structures of recombinant HAdV5 vectors have been determined using cryo-EM (11) and X-ray methods (12) that revealed the structures and organization of some of the cement proteins. Both studies agree closely on the organization of the MCPs and confirm the earlier cryo-EM observations (9, 10, 13), but neither provided...

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Switch from capsid protein import to adenovirus assembly by cleavage of nuclear transport signals

Cited by 79 publications

References 85 publications

Current Advances and Future Challenges in Adenoviral Vector Biology and Targeting

Current Advances and Future Challenges in Adenoviral Vector Biology and Targeting

The Role of Capsid Maturation on Adenovirus Priming for Sequential Uncoating

Structures and organization of adenovirus cement proteins provide insights into the role of capsid maturation in virus entry and infection

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