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Research Themes Infectious diseases

Capsid assembly in motion

SBKB [doi:10.1038/sbkb.2011.14]
Technical Highlight - April 2011
Short description: Using hydrogen–deuterium exchange, Gag immature, mature and cleavage-mutant particles are now examined to follow the dynamic changes that occur during capsid assembly.

Model of HIV-1 CA lattice arrangements showing the stages of CA maturation used in the study. Dark red, CA N-terminal domain (NTD); light red, CA C-terminal domain (CTD); blue, spacer peptide 1 (SP1).

Even when structural and biochemical analysis tools have been used to attack a molecular biological problem, insight into the overall dynamic changes that occur during the process can give new insight and understanding. HIV-1 remains a major health problem, and attempts to continue to gather new information to better understand it can only help to tackle it. The Gag polyprotein contains the matrix (MA), capsid (CA) and nucleocapsid (NC) structural domains and composes the immature, non-infectious particle. Gag is cleaved by the viral protease, and subsequent structural rearrangements result in CA subunits forming the core of the mature virion. CA consists of a C- and an N-terminal region (CTD and NTD, respectively). Structures of these domains plus a full-length CA have been elucidated previously and indicate that formation of a β-hairpin, as well as a rigid body motion of these domains, occurs during maturation. EM has given some insight into the arrangement of CA in the immature and mature particle, and crystallographic studies have even addressed the arrangement of CA in the mature particle. However, the transition between these states and the structure of the immature particle are less clear, though the maturation step is one step that could be targeted to combat formation of the infective virus. Prevelige and colleagues have now used hydrogen–deuterium exchange mass spectroscopy (H/D exchange MS) to examine three key stages in Gag maturation, comparing solvent accessibility and protein dynamics in different regions to thus elucidate a path to the mature capsid. The authors examined the matrix-capsid fusion protein (MACA) as well as CA5, a cleavage mutant, to reveal regions that are more or less protected in different states. The regions that became protected in immature particles were similar to those that are involved in interactions in the hexameric units that were previously observed in the structure of the mature particle, indicating that key interactions are already present in the immature capsid lattice. The β-hairpin that is known to be present in the mature CA structure and absent in the immature CA was not present in CA5. This indicates that the β-hairpin, which is known to be essential for viral maturation, is formed late in the rearrangement process and after cleavage. This also turns out to be true of the rigid body movement that brings NTD and CTD together. The authors argue that this is consistent with a model in which the β-hairpin facilitates stabilization of the final position of NTD, but its late formation indicates that it may not be a driving force of maturation. Instead, the β-hairpin may actually be a consequence of this process. Altogether, the data demonstrate that such approaches may help define the order of events in structural rearrangements and refine insights gained through structural data.

Sabbi Lall

References

  1. Monroe et al. Hydrogen/deuterium exchange analysis of HIV-1 capsid assembly and maturation.
    Structure 18, 1483-1491 (2010). doi:10.1016/j.str.2010.08.016

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