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J. Biol. Chem., Vol. 277, Issue 52, 50380-50385, December 27, 2002
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From the The amino-terminal domain of
apolipoprotein (apo) E4 is less susceptible to chemical and thermal
denaturation than the apoE3 and apoE2 domains. We compared the urea
denaturation curves of the 22-kDa amino-terminal domains of the apoE
isoforms at pH 7.4 and 4.0. At pH 7.4, apoE3 and apoE4 reflected an
apparent two-state denaturation. The midpoints of denaturation were 5.2 and 4.3 M urea, respectively. At pH 4.0, a pH value
known to stabilize folding intermediates, apoE4 and apoE3 displayed the
same order of denaturation but with distinct plateaus, suggesting the
presence of a stable folding intermediate. In contrast, apoE2 proved
the most stable and lacked the distinct plateau observed with the other
two isoforms and could be fitted to a two-state unfolding model.
Analysis of the curves with a three-state unfolding model (native,
intermediate, and unfolded) showed that the apoE4 folding intermediate
reached its maximal concentration (
Apolipoprotein E4 Forms a Molten Globule
A POTENTIAL BASIS FOR ITS ASSOCIATION WITH DISEASE*
§¶,§¶,§,
,, and§§§
Gladstone Institutes of Cardiovascular
Disease and Neurological Disease, San Francisco, California 94141-9100, the § Cardiovascular Research Institute and the
Department of Pathology, University of
California, San Francisco, California 94143, Lawrence Livermore
National Laboratory, Livermore, California 94551, and
** Allecure, Inc., Los Angeles, California 91355
90% of the mixture) at
3.75 M, whereas the apoE3 intermediate was maximal at 4.75 M (80%). These results are consistent with apoE4 being
more susceptible to unfolding than apoE3 and apoE2 and more prone to
form a stable folding intermediate. The structure of the apoE4 folding
intermediate at pH 4.0 in 3.75 M urea was characterized
using pepsin proteolysis, Fourier transform infrared spectroscopy, and
dynamic light scattering. From these studies, we conclude that the
apoE4 folding intermediate is a single molecule with the
characteristics of a molten globule. We propose a model of the apoE4
molten globule in which the four-helix bundle of the amino-terminal
domain is partially opened, generating a slightly elongated structure
and exposing the hydrophobic core. Since molten globules have been
implicated in both normal and abnormal physiological function, the
differential abilities of the apoE isoforms to form a molten globule
may contribute to the isoform-specific effects of apoE in disease.
*
This work was supported in part by grant NS35939 from the
National Institutes of Health (to K. H. W.).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.
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