Autoimmunity in Scleroderma
491
to be three different types of epitopes on
the C-terminus, each speciFc to a linear
sequence, a three-dimensional structure
newly formed by a dimer complex, and
the conformational structure formed by a
macromolecular complex in the presence
of GroEL.
2.4
CENP-A and B-cell Epitopes
CENP-A is also a component of the inner
plate of the trilaminar structure of the
kinetocore. It has 140 amino acids and
a molecular weight of 17 kDa (±ig. 5).
Because of the presence of the region
homologous to histone H3 in the C-
terminal half, it is considered to function
as a centromere-speciFc core histone. This
region shares 62% identity with histone
H3andisca
l
ledthe
histone fold
domain.
Although the N-terminal region from
1t
o4
8r
e
s
i
d
u
e
si
su
n
i
q
u
ef
o
rCENP
-
A, its localization to the centromere is
dependent on the histone fold domain.
Nevertheless, the two-third part of the C-
terminal peptide of CENP-A showed no
reactivity to ACA.
The
basic
amino
acids
in
the
N-
terminus may be involved in the pro-
tein–protein interaction with an acidic
protein(s) or the DNA binding activities.
Brendel et al. suggested that autoanti-
gens generally contain more long charge
runs or clusters of charged groups, which
may be exposed on their surface and be
strongly immunogenic, and consist of ex-
tended surface structures that are charge-,
proline-, or glycine-rich. Two peptides
composed of amino acid residues 3 to 17
(named peptide A) and residues 25 to 38
(peptide B) were synthesized and exam-
ined for the reactivity to ACA. Peptide A
contains seven arginine (R), one lysine,
and three proline (P), and two repeats
of PRRRS. Peptide B has a few charged
residues (two arginine and one histidine)
but contains two dipeptide Pro-Ser or one
Ser-Ser, leaving each of the three residues
(PSXXXPSXXXSS) and two repeats of Gly-
Pro-Ser. Interestingly, nearly 90% of ACA
showed reactivity to both peptides. These
two, epitopes 1 and 2, are the major au-
toepitopes. Peptide A was further used
by Valdivia et al. to produce experimental
ACA in rabbits and its strong antigenicity
was demonstrated. Additional epitope(s)
is present in the region between 39 to
52 amino acid residues, but very minor
populations of ACA have reactivities.
2.5
Centromere-associated Autoantigens
Heterochromatin protein 1 (HP1) was Frst
identiFed in
Drosophila
as a nonhistone
chromosomal protein that functions in
the establishment and maintenance of
higher-order chromatin structures play-
ing a role in chromosome segregation
and gene silencing. Three related pro-
teins
homologous
to
Drosophila
HP1
Fig. 5
Functional domains and
autoepitopes of CENP-A. The top
rectangle represents the full-length
human CENP-A antigen. Major
autoepitopes, which are recognized by
more than 80% of ACA, are shown as
black bars.
1
"Histone fold" domain
Centromere localization
25
31
7
4 repeats
of S/T-P
140
49
38
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