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J. Biol. Chem., Vol. 278, Issue 20, 18249-18255, May 16, 2003
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From the Department of Biochemistry and Molecular Biology,
University of Oklahoma Health Sciences Center,
Oklahoma City, Oklahoma 73190
For many protein multimers, association and
dissociation reactions fail to reach the same end point; there is
hysteresis preventing one and/or the other reaction from equilibrating.
We have studied in vitro assembly of dimeric hepatitis B
virus (HBV) capsid protein and dissociation of the resulting T = 4 icosahedral capsids. Empty HBV capsids composed of 120 capsid protein
dimers were more resistant to dissociation by dilution or denaturants
than anticipated from assembly experiments. Using intrinsic
fluorescence, circular dichroism, and size exclusion chromatography, we
showed that denaturants dissociate the HBV capsids without unfolding
the capsid protein; unfolding of dimer only occurred at higher
denaturant concentrations. The apparent energy of interaction between
dimers measured in dissociation experiments was much stronger than when
measured in assembly studies. Unlike assembly, capsid dissociation did not have the concentration dependence expected for a 120-subunit complex; consequently the apparent association energy systematically varied with reactant concentration. These data are evidence of hysteresis for HBV capsid dissociation. Simulations of capsid assembly
and dissociation reactions recapitulate and provide an explanation for
the observed behavior; these results are also applicable to oligomeric
and multidomain proteins. In our calculations, we find that
dissociation is impeded by temporally elevated concentrations of
intermediates; this has the paradoxical effect of favoring re-assembly
of those intermediates despite the global trend toward dissociation.
Hysteresis masks all but the most dramatic decreases in contact energy.
In contrast, assembly reactions rapidly approach equilibrium. These
results provide the first rigorous explanation of how virus capsids can
remain intact under extreme conditions but are still capable of
"breathing." A biological implication of enhanced stability is that
a triggering event may be required to initiate virus uncoating.
Observed Hysteresis of Virus Capsid Disassembly Is
Implicit in Kinetic Models of Assembly*
*
This research was supported by American Cancer Society Grant
RSG-99-339-04-MBC.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 405-271-9030;
Fax: 405-271-3910; E-mail: adam-zlotnick@ouhsc.edu.
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