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Virus maturation: dynamics and mechanism of a stabilizing structural transition that leads to infectivity.

ABSTRACT: For many viruses, the final stage of assembly involves structural transitions that convert an innocuous precursor particle into an infectious agent. This process -- maturation -- is controlled by proteases that trigger large-scale conformational changes. In this context, protease inhibitor antiviral drugs act by blocking maturation. Recent work has succeeded in determining the folds of representative examples of the five major proteins -- major capsid protein, scaffolding protein, portal, protease and accessory protein -- that are typically involved in capsid assembly. These data provide a framework for detailed mechanistic investigations and elucidation of mutations that affect assembly in various ways. The nature of the conformational change has been elucidated: it entails rigid-body rotations and translations of the arrayed subunits that transfer the interactions between them to different molecular surfaces, accompanied by refolding and redeployment of local motifs. Moreover, it has been possible to visualize maturation at the submolecular level in movies based on time-resolved cryo-electron microscopy.

SUBMITTER: Steven AC

PROVIDER: S-EPMC1351302 | biostudies-literature | 2005 Apr

REPOSITORIES: biostudies-literature

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Virus maturation: dynamics and mechanism of a stabilizing structural transition that leads to infectivity.

Steven Alasdair C AC Heymann J Bernard JB Cheng Naiqian N Trus Benes L BL Conway James F JF

Current opinion in structural biology 20050401 2

For many viruses, the final stage of assembly involves structural transitions that convert an innocuous precursor particle into an infectious agent. This process -- maturation -- is controlled by proteases that trigger large-scale conformational changes. In this context, protease inhibitor antiviral drugs act by blocking maturation. Recent work has succeeded in determining the folds of representative examples of the five major proteins -- major capsid protein, scaffolding protein, portal, protea ...[more]

PMID: 15837183

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Project description:Nudaurelia capensis omega virus is a T=4, icosahedral virus with a bipartite, positive-sense RNA genome. Expression of the coat protein gene in a baculovirus system was previously shown to result in the formation of procapsids when purified at pH 7.6. Procapsids are round, porous particles (480 A diameter) and have T=4 quasi-symmetry. Reduction of pH from 7.6 to 5.0 resulted in virus-like particles (VLP(5.0)) that are morphologically identical with authentic virions, with an icosahedral-shaped capsid and a maximum dimension of 410 A. VLP(5.0) undergoes a maturation cleavage between residues N570 and F571, creating the covalently independent gamma peptide (residues 571-641) that remains associated with the particle. This cleavage also occurs in authentic virions, and in each case, it renders the morphological change irreversible (i.e., capsids do not expand when the pH is raised back to 7.6). However, a non-cleavable mutant, N570T, undergoes the transition reversibly (NT(7.6)<-->NT(5.0)). We used electron cryo-microscopy and three-dimensional image reconstruction to study the icosahedral structures of NT(7.6), NT(5.0), and VLP(5.0) at about 8, 6, and 6 A resolution, respectively. We employed the 2. 8-A X-ray model of the mature virus, determined at pH 7.0 (XR(7.0)), to establish (1) how and why procapsid and capsid structures differ, (2) why lowering pH drives the transition, and (3) why the non-cleaving NT(5.0) is reversible. We show that procapsid assembly minimizes the differences in quaternary interactions in the particle. The two classes of 2-fold contacts in the T=4 surface lattice are virtually identical, both mediated by similarly positioned but dynamic gamma peptides. Furthermore, quasi and icosahedral 3-fold interactions are indistinguishable. Maturation results from neutralizing the repulsive negative charge at subunit interfaces with significant differentiation of quaternary interactions (one 2-fold becomes flat, mediated by a gamma peptide, while the other is bent with the gamma peptide disordered) and dramatic stabilization of the particle. The gamma peptide at the flat contact remains dynamic when cleavage cannot occur (NT(5.0)) but becomes totally immobilized by noncovalent interactions after cleavage (VLP(5.0)).

Dataset Information

Virus maturation: dynamics and mechanism of a stabilizing structural transition that leads to infectivity.

Publications

Virus maturation: dynamics and mechanism of a stabilizing structural transition that leads to infectivity.

Similar Datasets

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