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J. Biol. Chem., Vol. 277, Issue 1, 161-168, January 4, 2002
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From the Department of Biochemistry, Tulane University Health
Sciences Center, New Orleans, Louisiana 70112-2699
Antigen three-dimensional structure potentially
limits the access of endoproteolytic processing enzymes to cleavage
sites and of class II major histocompatibility antigen-presenting
proteins to helper T-cell epitopes. Helper T-cell epitopes in
bacteriophage T4 Hsp10 have been mapped by restimulation of splenocytes
from CBA/J and C57BL/6J mice immunized in conjunction with mutant
(R192G) heat-labile enterotoxin from Escherichia coli.
Promiscuously immunogenic sequences were associated with unstable loops
in the three-dimensional structure of T4 Hsp10. The immunodominant
sequence lies on the N-terminal flank of the 22-residue mobile loop,
which is sensitive to proteolysis in divergent Hsp10s. Several mobile
loop deletions that inhibited proteolysis in vitro caused
global changes in the helper T-cell epitope map. A mobile loop deletion
that strongly stabilized the protein dramatically reduced the
immunogenicity of the flanking immunodominant helper T-cell epitope,
although the protein retained good overall immunogenicity. Antisera
against the mobile loop deletion variants exhibited increased
cross-reactivity, most especially the antisera against the strongly
stabilized variant. The results support the hypothesis that unstable
loops promote the presentation of flanking epitopes and suggest that
loop deletion could be a general strategy to increase the breadth and
strength of an immune response.
Structural Basis for Helper T-cell and Antibody Epitope
Immunodominance in Bacteriophage T4 Hsp10
ROLE OF DISORDERED LOOPS*
*
This work was supported by National Institutes of Health
Grant R01-AI42350.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: Dept. of Biochemistry,
Tulane University Health Sciences Center, 1430 Tulane Ave., New
Orleans, LA 70112-2699. Tel.: 504-586-3990; Fax: 504-584-2739; E-mail: landry@tulane.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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