NDLI: Design of in vitro Symmetric Complexes and Analysis by Hybrid Methods Reveal Mechanisms of HIV Capsid Assembly

Content Provider	PubMed Central
Author	Yeager, Mark
Copyright Year	2011
Abstract	Unlike the capsids of icosahedral viruses, retroviral capsids are pleomorphic, with variably curved, closed fullerene shells composed of ~250 hexamers and exactly 12 pentamers of the viral CA protein. Structures of CA oligomers have been difficult to obtain because the subunit-subunit interactions are inherently weak, and CA tends to spontaneously assemble into capsid-like particles. Guided by a cryoEM-based model of the hexagonal lattice of HIV-1 CA, we used a two-step biochemical strategy to obtain soluble CA hexamers and pentamers for crystallization. First, each oligomer was stabilized by engineering disulfide cross-links between the N-terminal domains of adjacent subunits. Second, the cross-linked oligomers were prevented from polymerizing into hyperstable, capsid-like structures by mutations that weakened the dimeric association between the C-terminal domains that link adjacent oligomers. The X-ray structures revealed that the oligomers are comprised of a fairly rigid, central symmetric ring of N-terminal domains encircled by mobile C-terminal domains. Assembly of the quasi-equivalent oligomers requires remarkably subtle rearrangements in inter-subunit quaternary bonding interactions, and appears to be controlled by an electrostatic switch that favors hexamers over pentamers. An atomic model of the complete HIV-1 capsid was then built using the fullerene cone as a template. Rigid-body rotations around two assembly interfaces are sufficient to generate the full range of continuously varying lattice curvature in the fullerene cone. The steps in determining this HIV-1 capsid atomic model exemplify how structural biology can be leveraged by the use of hybrid methods, a powerful approach for exploring the structure of pleomorphic macromolecular complexes.
Related Links	http://dx.doi.org/10.1016/j.jmb.2011.04.073
Ending Page	552
Page Count	19
Starting Page	534
File Format	PDF
ISSN	00222836
e-ISSN	10898638
Journal	Journal of molecular biology
Issue Number	4
Volume Number	410
Language	English
Publisher Date	2011-07-01
Access Restriction	Open
Subject Keyword	Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Structural Biology Molecular Biology Biophysics

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