The active adenovirus protease is the intact L3 23K protein

Webster, Ailsa; Kemp, Graham D.

doi:10.1099/0022-1317-74-7-1415

Cited by 25 publications

(16 citation statements)

References 20 publications

(24 reference statements)

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“…Adenovirus pVI functions during later stages of infection by facilitating virus assembly (Hannan et al 1983; Webster et al 1993; Ding et al 1996; Wodrich et al 2003). Amino acids between residues 48-74 and 233-239 of pVI mediate hexon binding and facilitate hexon nuclear import where capsid assembly occurs (Matthews et al 1994; Matthews et al 1995; Wodrich et al 2003).…”

Section: Discussionmentioning

confidence: 99%

An N-terminal domain of adenovirus protein VI fragments membranes by inducing positive membrane curvature

Maier

Galan

Wodrich³

et al. 2010

Virology

104

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Adenovirus (Ad) membrane penetration during cell entry is poorly understood. Here we show that antibodies which neutralize the membrane lytic activity of the Ad capsid protein VI interfere with Ad endosomal membrane penetration. In vitro studies using a peptide corresponding to an N-terminal amphipathic α-helix of protein VI (VI-Φ), as well as other truncated forms of protein VI suggest that VI-Φ is largely responsible for protein VI binding to and lysing of membranes. Additional studies suggest that VI-Φ lies nearly parallel to the membrane surface. Protein VI fragments membranes and induces highly curved structures. Further studies suggest that Protein VI induces positive membrane curvature. These data support a model in which protein VI binds membranes, inducing positive curvature strain which ultimately leads to membrane fragmentation. These results agree with previous observations of Ad membrane permeabilization during cell entry and provide an initial mechanistic description of a nonenveloped virus membrane lytic protein.

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Section: Discussionmentioning

confidence: 99%

An N-terminal domain of adenovirus protein VI fragments membranes by inducing positive membrane curvature

Maier

Galan

Wodrich³

et al. 2010

Virology

104

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“…The The human adenovirus serotype 2 proteinase (AVP) 1 is required for the synthesis of infectious virus (1,2). Biochemical studies with the recombinant form of AVP showed that AVP requires two cofactors for maximal proteinase activity (3)(4)(5)(6). One cofactor is the eleven amino acid residue peptide pVIc, originating from the C terminus of the precursor protein pVI.…”

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confidence: 99%

DNA Binding Provides a Molecular Strap Activating the Adenovirus Proteinase

Gupta

Mangel

McGrath

et al. 2004

Molecular & Cellular Proteomics

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Human adenovirus proteinase (AVP) requires two cofactors for maximal activity: pVIc, a peptide derived from the C terminus of adenovirus precursor protein pVI, and the viral DNA. Synchrotron protein footprinting was used to map the solvent accessible cofactor binding sites and to identify conformational changes associated with the binding of cofactors to AVP. The binding of pVIc alone or pVIc and DNA together to AVP triggered significant conformational changes adjacent to the active site cleft sandwiched between the two AVP subdomains. In addition, upon binding of DNA to AVP, it was observed that specific residues on each of the two major subdomains were significantly protected from hydroxyl radicals. Based on the locations of these protected side-chain residues and conserved aromatic and positively charged residues within AVP, a three-dimensional model of DNA binding was con-

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“…Although it appears to be a cysteine protease (8), the catalytic histidine and cysteine (His-54 and Cys-122) are in the reverse order of that found in the archetypal cysteine protease, papain (Cys-25 and His-159), which has led to them being classified in separate families within the category of cysteine protease (9). Perhaps the most interesting facet of its mode of action, however, is that in contrast to most other proteases it does not require proteolytic activation (10). The development of significant proteolytic activity depends on the participation of an 11-residue peptide (GVQSLKRRRCF), which is derived from the C terminus of the viral capsid protein pVI (11,12).…”

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confidence: 99%

Activation of the Adenovirus Protease Requires Sequence Elements from Both Ends of the Activating Peptide

Cabrita¹,

Iqbal

Reddy

et al. 1997

Journal of Biological Chemistry

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The adenovirus protease requires activation by an 11-residue peptide, GVQSLKRRRCF, to achieve maximum proteolytic activity. Derived from the C terminus of the viral protein pVI, the activating peptide (pVI-CT) forms a disulfide bond with cysteine 104 of the protease and causes a conformational change that accompanies the development of proteolytic activity. Results presented here show that the interaction of pVI-CT with the protease is dependent not only on the cysteine 10 but also on glycine 1 and valine 2. Removal of these residues, acetylation of the N-terminal glycine, or mutation of the valine to alanine or threonine significantly reduces or abolishes activation. Peptides lacking Gly-1 and Val-2 still form a disulfide bond with the protease but do not cause a conformational change in the protease also they are not effective inhibitors of activation as the interaction is readily reversed by full-length pVI-CT. These results suggest that pVI-CT causes activation by binding to two distinct regions of the protease and in doing so stabilizes the catalytic site. The reversible nature of the activation, suggested by the results presented here, may well reflect an in vivo regulatory mechanism.The protease coded by adenovirus plays an essential role in the replication cycle of the virus (1) and has distinctive properties that make it of intrinsic scientific interest and an attractive target for antiviral therapy. It is known to cleave several capsid proteins (2) suggesting that it has a role in virion maturation; it cleaves the preterminal protein (pTP), the protein primer for DNA replication, thereby altering the affinity of that protein for the viral polymerase (3). It has also been reported to cleave the cellular protein cytokeratin 18 (4) raising the intriguing possibility that it has a role in the escape of the mature virus from the cell.Its properties are distinctive in several ways. It has an unusual substrate specificity (5, 6) that depends primarily on recognizing a hydrophobic residue (M, L, or I) in the P 4 position (7) and accepting only a glycine in P 2 . Although it appears to be a cysteine protease (8), the catalytic histidine and cysteine (His-54 and Cys-122) are in the reverse order of that found in the archetypal cysteine protease, papain (Cys-25 and His-159), which has led to them being classified in separate families within the category of cysteine protease (9). Perhaps the most interesting facet of its mode of action, however, is that in contrast to most other proteases it does not require proteolytic activation (10). The development of significant proteolytic activity depends on the participation of an 11-residue peptide (GVQSLKRRRCF), which is derived from the C terminus of the viral capsid protein pVI (11, 12). There have also been reports that viral DNA is involved in the catalytic mechanism (12, 13), but other reports (3) suggest that DNA is not necessary for catalysis but may help to stabilize the protease in vitro and could enhance the interaction of protease and substrates in vivo.Previo...

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The active adenovirus protease is the intact L3 23K protein

Cited by 25 publications

References 20 publications

An N-terminal domain of adenovirus protein VI fragments membranes by inducing positive membrane curvature

An N-terminal domain of adenovirus protein VI fragments membranes by inducing positive membrane curvature

DNA Binding Provides a Molecular Strap Activating the Adenovirus Proteinase

Activation of the Adenovirus Protease Requires Sequence Elements from Both Ends of the Activating Peptide

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