Regulation of a Viral Proteinase by a Peptide and DNA in One-dimensional Space

Baniecki, Mary Lynn; McGrath, William J.; Mangel, Walter F.

doi:10.1074/jbc.m112.407429

Cited by 12 publications

(11 citation statements)

References 45 publications

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“…In immature virus particles, pVI slides along the viral genome through interactions of the c-terminus of pVI with the DNA 10, 11 . As pVI encounters AVP, AVP cleaves the 11 C-terminal residues from pVI (pVIc), which then binds and covalently links to AVP via a disulfide bridge yielding maximum AVP activity 8, 10–16 . AVP then processes the precursors of IIIa, VI, VII, VIII, µ and terminal protein into their mature forms 7 .…”

Section: Introductionmentioning

confidence: 99%

The Cleaved N-Terminus of pVI Binds Peripentonal Hexons in Mature Adenovirus

Snijder

Benevento

Moyer

et al. 2014

Journal of Molecular Biology

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Mature human adenovirus particles contain four minor capsid proteins, in addition to the three major capsid proteins (penton base, hexon and fiber) and several proteins associated with the genomic core of the virion. Of the minor capsid proteins, VI plays several crucial roles in the infection cycle of the virus, including hexon nuclear targeting during assembly, activation of the adenovirus proteinase (AVP) during maturation and endosome escape following cell entry. VI is translated as a precursor (pVI) that is cleaved at both the N- and C-termini by AVP. Whereas the role of the C-terminal fragment of pVI, pVIc, is well established as an important co-factor of AVP, the role of the N-terminal fragment, pVIn, is currently elusive. In fact, the fate of pVIn following proteolytic cleavage is completely unknown. Here, we use a combination of proteomics-based peptide identification, native mass spectrometry and hydrogen-deuterium exchange mass spectrometry to show that pVIn is associated with mature human adenovirus, where it binds at the base of peripentonal hexons in a pH-dependent manner. Our findings suggest a possible role for pVIn in targeting pVI to hexons for proper assembly of the virion and timely release of the membrane lytic mature VI molecule.

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Section: Introductionmentioning

confidence: 99%

The Cleaved N-Terminus of pVI Binds Peripentonal Hexons in Mature Adenovirus

Snijder

Benevento

Moyer

et al. 2014

Journal of Molecular Biology

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“…A model has been proposed for the activation of AVP upon the binding of pVIc that is consistent with the structural differences between AVP and AVP-pVIc complexes [ 94 ].The structural changes that occur upon the binding of pVIc to AVP are localized for the most part to the β-strand domain and appear to involve a path over 62 amino acids long. This implies there may be an “activation” pathway along which contiguous conformation changes occur, analogous to falling dominos.…”

Section: Unveiling the Enzymatic Mechanism Of Avpmentioning

confidence: 87%

“…Later on, AVP was crystallized in the absence of any cofactor, and its structure solved to atomic resolution, 0.98 Å [ 94 ]. Both the crystal structure of AVP and the AVP-pVIc complex have an α plus β fold; the major structural differences between them lie in the β-sheet domain.…”

Section: Unveiling the Enzymatic Mechanism Of Avpmentioning

confidence: 99%

“…Comparison of the crystal structures of inactive AVP [ 94 ] and active AVP-pVIc complexes [ 86 , 87 , 88 ] reveals a number of differences which could be considered as targets for drug interactions. These sites, which cover more than 40% of the surface of AVP, include the active site [ 86 , 87 , 88 , 94 ], pVIc binding site, DNA binding region [ 96 , 101 ], and the activation pathway [ 94 ]. Using structure-based drug design, a lead compound was identified that was predicted to bind to both the active site and the conserved site at which the N -terminus of pVIc binds [ 124 ].…”

Section: Unveiling the Enzymatic Mechanism Of Avpmentioning

confidence: 99%

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Structure, Function and Dynamics in Adenovirus Maturation

Mangel

Martín

2014

Viruses

107

134

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Here we review the current knowledge on maturation of adenovirus, a non-enveloped icosahedral eukaryotic virus. The adenovirus dsDNA genome fills the capsid in complex with a large amount of histone-like viral proteins, forming the core. Maturation involves proteolytic cleavage of several capsid and core precursor proteins by the viral protease (AVP). AVP uses a peptide cleaved from one of its targets as a “molecular sled” to slide on the viral genome and reach its substrates, in a remarkable example of one-dimensional chemistry. Immature adenovirus containing the precursor proteins lacks infectivity because of its inability to uncoat. The immature core is more compact and stable than the mature one, due to the condensing action of unprocessed core polypeptides; shell precursors underpin the vertex region and the connections between capsid and core. Maturation makes the virion metastable, priming it for stepwise uncoating by facilitating vertex release and loosening the condensed genome and its attachment to the icosahedral shell. The packaging scaffold protein L1 52/55k is also a substrate for AVP. Proteolytic processing of L1 52/55k disrupts its interactions with other virion components, providing a mechanism for its removal during maturation. Finally, possible roles for maturation of the terminal protein are discussed.

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“…This region of the virus is not icosahedarally ordered and thus it has not been possible to analyze its structure. However, it is known that protein VI and the C-terminus of this protein in particular, acts as a molecular sled to facilitate the translocation of the viral cysteine protease along DNA during virus capsid maturation (71,72). …”

Section: Structure and Localization Of Protein VI In The Hadv Capsidmentioning

confidence: 99%

Adenovirus membrane penetration: Tickling the tail of a sleeping dragon

Wiethoff

Nemerow

2015

Virology

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As is the case for nearly every viral pathogen, non-enveloped viruses (NEV) must maintain their integrity under potentially harsh environmental conditions while retaining the ability to undergo rapid disassembly at the right time and right place inside host cells. NEVs generally exist in this metastable state until they encounter key cellular stimuli such as membrane receptors, decreased intracellular pH, digestion by cellular proteases, or a combination of these factors. These stimuli trigger conformational changes in the viral capsid that exposes a sequestered membrane-perturbing protein. This protein subsequently modifies the cell membrane in such a way as to allow passage of the virion and accompanying nucleic acid payload into the cell cytoplasm. Different NEVs employ variations of this general pathway for cell entry (1), however this review will focus on significant new knowledge obtained on cell entry by human adenovirus(HAdV).

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Regulation of a Viral Proteinase by a Peptide and DNA in One-dimensional Space

Cited by 12 publications

References 45 publications

The Cleaved N-Terminus of pVI Binds Peripentonal Hexons in Mature Adenovirus

The Cleaved N-Terminus of pVI Binds Peripentonal Hexons in Mature Adenovirus

Structure, Function and Dynamics in Adenovirus Maturation

Adenovirus membrane penetration: Tickling the tail of a sleeping dragon

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