Multiple Sites of the Cleavage of 21- and 25-Mer
Encephalytogenic Oligopeptides Corresponding to
Human Myelin Basic Protein (MBP) by Specific Anti-MBP
Antibodies from Patients with Systemic Lupus
Anna M. Timofeeva1, Pavel S. Dmitrenok2, Ludmila P. Konenkova3, Valentina N. Buneva1,4,
Georgy A. Nevinsky1,4*
1Institute of Chemical Biology and Fundamental Medicine, Siberian Division of Russian Academy of Sciences, Novosibirsk, Russia, 2Pacific Institute of Bioorganic
Chemistry, Far East Division, Russian Academy of Sciences, Vladivostok, Russia, 3Institute of Clinical Immunology, Siberian Division of Russian Medical Academy of
Sciences, Novosibirsk, Russia, 4Novosibirsk State University, Novosibirsk, Russia
IgGs from patients with multiple sclerosis and systemic lupus erythematosus (SLE) purified on MBP-Sepharose in contrast to
canonical proteases hydrolyze effectively only myelin basic protein (MBP), but not many other tested proteins. Here we have
shown for the first time that anti-MBP SLE IgGs hydrolyze nonspecific tri- and tetrapeptides with an extreme low efficiency
and cannot effectively hydrolyze longer 20-mer nonspecific oligopeptides corresponding to antigenic determinants (AGDs)
of HIV-1 integrase. At the same time, anti-MBP SLE IgGs efficiently hydrolyze oligopeptides corresponding to AGDs of MBP.
All sites of IgG-mediated proteolysis of 21-and 25-mer encephalytogenic oligopeptides corresponding to two known AGDs
of MBP were found by a combination of reverse-phase chromatography, TLC, and MALDI spectrometry. Several clustered
major, moderate, and minor sites of cleavage were revealed in the case of 21- and 25-mer oligopeptides. The active sites of
anti-MBP abzymes are localised on their light chains, while heavy chains are responsible for the affinity of protein substrates.
Interactions of intact globular proteins with both light and heavy chains of abzymes provide high affinity to MBP and
specificity of this protein hydrolysis. The affinity of anti-MBP abzymes for intact MBP is approximately 1000-fold higher than
for the oligopeptides. The data suggest that all oligopeptides interact mainly with the light chains of different monoclonal
abzymes of total pool of IgGs, which possesses a lower affinity for substrates, and therefore, depending on the oligopeptide
sequences, their hydrolysis may be less specific than globular protein and can occur in several sites.
Citation: Timofeeva AM, Dmitrenok PS, Konenkova LP, Buneva VN, Nevinsky GA (2013) Multiple Sites of the Cleavage of 21- and 25-Mer Encephalytogenic
Oligopeptides Corresponding to Human Myelin Basic Protein (MBP) by Specific Anti-MBP Antibodies from Patients with Systemic Lupus Erythematosus. PLoS
ONE 8(3): e51600. doi:10.1371/journ `l.pone.0051600
Editor: Vladimir N. Uversky, University of South Florida College of Medicine, United States of America
Received October 17, 2012; Accepted November 1, 2012; Published March 8, 2013
Copyright: ? 2013 Timofeeva et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This research was made possible in part by grants from the Presidium of the Russian Academy of Sciences (Molecular and Cellular Biology Program, 6.7;
Fundamental Sciences to Medicine, 5.13), Russian Foundation for Basic Research (10-04-00281), and funds from the Siberian Division of the Russian Academy of
Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: firstname.lastname@example.org
It is known, that the occurrence of auto-Abs in increased
concentration is a distinctive feature of various autoimmune
diseases (ADs) (reviewed in [1–8]). It was shown that small
fractions of auto-Abs can possess different catalytic activities [1–8].
Catalytically active artificial antibodies (Abs) or abzymes (Abzs)
against transition chemical states of different reactions were
studied intensively (reviewed in ). Healthy humans and patients
with many diseases with insignificant autoimmune reactions
usually lack abzymes or develop Abzs with very low catalytic
activities, with these activities being often on a borderline of the
sensitivity of detection methods (reviewed in [2–8]). Natural
abzymes hydrolyzing DNA, RNA, polysaccharides, oligopeptides
(OPs), and proteins are described from the sera of patients with
several autoimmune (systemic lupus erythematosus, Hashimoto’s
thyroiditis, polyarthritis, multiple sclerosis, asthma, rheumatoid
arthritis, etc.) and viral diseases with a pronounced immune system
disturbance (viral hepatitis, AIDS, and tick-borne encephalitis)
(reviewed in [2–10]). Abzymes may play a significant positive and/
or negative role in broadening Ab properties, forming specific
pathogenic patterns and clinical settings in different autoimmune
Multiple sclerosis (MS) and systemic lupus erythematosus (SLE)
are well known ADs. MS is a chronic demyelinating disease of the
central nervous system. Its etiology remains unclear, and the most
widely accepted theory of MS pathogenesis assigns the main role
in the destruction of myelin to the inflammation related to
autoimmune reactions . Several recent findings imply an
important role of B cells and auto-Abs against myelin autoantigens
PLOS ONE | www.plosone.org1 March 2013 | Volume 8 | Issue 3 | e51600
including myelin basic protein (MBP) in the pathogenesis of MS
SLE is a systemic autoimmune polyetiologic diffuse disease
characterized by disorganization of conjunctive tissues with the
paramount damage to skin and visceral capillaries . The
polyetiologic and polysyndromic character of SLE leads to highly
variable manifestations of this disease in terms of many
biochemical, immunological, and clinical indices. SLE is usually
considered to be related to patient’s autoimmunization with DNA,
since the sera of such patients usually contain DNA and anti-DNA
Abs in high concentrations . At the same time, in comparison
with healthy donors, an increased concentration of auto-Abs was
observed for various antigens (% of patients): DNA (60),
cardiolipin (48), thyroglobulin (42), microsomal fraction of
thyrocytes (48), and rheumatoid factor (23) .
It should be mentioned, that SLE and MS demonstrated some
similarity in the development of the same medical, biochemical
and immunological indexes. MS is a chronic disease of the central
nervous system leading to the manifestation of different nervous
and psychiatric disturbances. However, neuropsychiatric involve-
ment occurs in about 50% of SLE patients and carries a poor
prognosis (reviewed in ). SLE predominantly affects the central
nervous system, and within its cerebral complications it has a
particular propensity-perhaps more than any other systemic
inflammatory disease– to cause psychiatric disorders .
Peripheral nervous system involvement is much less common.
The distinctive production of diverse auto-Abs seems to be related
to defective clearance of apoptotic cells. Antibody-mediated neural
cell injury and rheological disturbances represent the two principal
suggested mechanisms of tissue injury . Interplay between
these processes, underlying genetic factors, their modification by
hormones, complicated by a number of secondary factors, may
explain the wide spectrum of features encountered in this disease.
Some indicators of disease common to SLE and MS were
For diagnostics of MS, thirteen Poser’s medical indices are often
used , but clinically definite MS diagnosis is usually based on
the tomographic detection of specific plaques in the brain, which
appear on late stages of not only this disease, but also in SLE
patients. Similarly to SLE, the high-affinity anti-DNA Abs has
been recently identified as a major component of the intrathecal
IgGs in MS patient’s brains and cells of the cerebrospinal fluid
. It was recently shown that titers of Abs against human myelin
basic protein in SLE patients 4.2-fold higher than in healthy
individuals, but 2.1-fold lower than in patients with MS . In
addition, abzymes from the sera of patients with SLE and MS
possess by the same catalytic activities (see below).
It was shown that SLE IgGs and IgMs effectively hydrolyzed
DNA, RNA, and polysaccharides [18–22]. Similarly to SLE,
homogeneous IgGs from the sera and the cerebrospinal fluid of
MS patients were active in the hydrolysis of DNA, RNA, and
polysaccharides [23–25]. Whereas only 18 and 53% of MS
patients contained increased concentrations of Abs to native and
denatured DNA, respectively, as compared with healthy donors,
DNase abzymes were found in ,80–90% of MS patients [23–24].
Since DNase abzymes of MS patients  similarly to SLE patients
 are cytotoxic and induce apoptosis, they can play an
important role in SLE and MS pathogenesis.
It has been recently shown that MBP-hydrolyzing activity is an
intrinsic property of IgGs, IgMs, and IgAs from the sera of MS
patients [27–30] and the specific sites of the neural antigen cleaved
by abzymes have been established . Recognition and
degradation of MBP peptides by serum auto-Abs was confirmed
as a novel biomarker for MS . In MS, anti-MBP abzymes with
protease activity can attack MBP of the myelin-proteolipid sheath
of axons. The established MS drug Copaxone appears to be a
specific inhibitor of MBP-hydrolyzing activity of the abzymes .
Consequently, MBP-hydrolyzing abzymes may play an important
negative role in MS pathogenesis. At the same time, the similarity
in some immunological indexes between MS and SLE can speak
in favour of that anti-MBP Abs with proteolytic activity can occur
in SLE patients. Recently, it was shown that electrophoretically
and immunologically homogeneous IgGs (approximately 86% of
SLE patients) purified using several affinity resins including
Sepharose with immobilized MBP (MBP-Sepharose) specifically
hydrolyze only MBP but not many other tested proteins .
Several rigid criteria were applied to show that the MBP-
hydrolyzing activity is an intrinsic property of SLE IgGs but not
from healthy donors. It was shown, that the immune systems of
individual SLE similarly to MS patients can generate a variety of
anti-MBP abzymes with different proteolytic properties, which can
attack MBP of myelin-proteolipid shell of axons and play an
important role in pathogenesis not only MS but also SLE patients.
Anti-MBP abzymes from the sera of MS patients hydrolyze
MBP at several sites localized within four known immunodomi-
nant regions of MBP . In addition, it was shown that anti-
MBP abzymes from the sera of SLE patients hydrolyze MBP at the
same four immunodominant sites of MBP . Four peptides
corresponding to known immunodominant regions of MBP are
encephalytogenic and can play a negative role in the MS and SLE
Taking this into account, it was interesting to study the Ab-
dependent hydrolysis of MBP specific sequences in more detail. In
this paper, we have analyzed site-specific degradation of two
oligopeptides (21- and 25-mer) corresponding to two AGDs of
MBP using combination of reverse-phase
(RPhC), thin-layer chromatography (TLC), MALDI spectrometry,
affinity chromatography, and enzymic kinetics.
In this work, electrophoretically and immunologically homoge-
neous polyclonal IgGs (pIgGs) were purified from the sera SLE
and MS patients as well as healthy donors by sequential
chromatography of the serum proteins on Protein G-Sepharose
under conditions that remove non-specifically bound proteins,
followed by gel filtration under the conditions that destroy
immune complexes as in . Electrophoretical and immunological
homogeneity of the pIgGs was confirmed respectively by SDS-
PAGE with silver staining and by Western blotting similarly to
[9,27–30]. To analyze an ‘‘average’’ situation, we have prepared a
mixture of equal amounts of homogeneous pIgGs from the sera of
ten SLE (sle-IgGmix), ten MS (ms-IgGmix) patients, and ten healthy
donors (hd-IgGmix). Then sle-IgGmix, ms-IgGmix, and hd-IgGmix
preparations having affinity for hMBP were separated by affinity
chromatography on MBP-Sepharose as in . The fractions of
IgGmixeluted from MBP-Sepharose with 3 M NaCl were used in
this study. To exclude possible artefacts due to traces of
contaminating proteases, these fractions were separated by SDS-
PAGE and their proteolytic activity was detected after the
extraction of proteins from the excised gel slices as in ; only
sle-IgGmix and ms-IgGmix preparations were active, when hd-
IgGmixwas catalytically inactive. The detection of MBP-hydro-
lyzing activity of these Abs similarly to  in the gel region
corresponding only to IgGs (150 kDa) together with the absence of
any other band of the activity or protein, provided a direct
evidence that all pIgG preparations used are not contaminated
Multiple Sites of Myelin Basic Protein Cleavage
PLOS ONE | www.plosone.org2March 2013 | Volume 8 | Issue 3 | e51600
KIIGQVRDQAE (in-OP2) [33,34]. All mentioned OPs contained
fluorescent residue 6-O-(Carboxymethyl)fluorescein ethyl ester (X)
on its N-terminus. In addition, three short fluorogenic peptidyl-4-
methylcoumaryl-7-amides (MCA) were used as nonspecific con-
(shOP2), Boc-Ile-Glu-Gly-Arg-MCA (shOP3).
The cleavage products of different OPs were separated by TLC
on Kieselgel F60 plates using acetic acid – n-butanol – H2O (1:4:5)
system. The plates were dried and photographed. To quantify the
intensities of the fluorescent spots after TLC, X-OP21, X-OP25,
and other OPs incubated without IgGs (or with hd-IgGmix) was
used as controls. Photographs of the plates were imaged by
scanning and quantified using GelPro v3.1 software.
In some experiments the cleavage products of specific X-OP21
and X-OP25 were first separated by reverse-phase chromatogra-
phy on Nucleosil C-18 column (4.66250 mm) using 0.05%
trifluoroacetic acid and gradient of acetonitrile concentration (0 -
80%). The relative amount of various cleavage products was
calculated by the fluorescence. Excitation was performed at
320 nm and fluorescence emission detected at 490 nm. The
fractions corresponding to different peaks were collected, evapo-
rated to minimal volume and products of the hydrolysis were
analyzed by TLC (see above) and by MALDI spectrometry (see
MALDI-TOF analysis Ab-dependent hydrolysis of OPs
In all cases the products of OP hydrolysis were analysed by
MALDI-TOF mass spectrometry using a ReflexIII system (Bruker,
Germany) equipped with a 337-nm nitrogen laser (VSL-337ND,
Laser Science, Newton, MA), 3 ns pulse duration. Saturated
solution of cyano-4-hydroxycinnamic acid in a mixture of 0.1%
acetonitrile and trifluoroacetic acid (1:2) was used as the matrix.
To 1 ml of the reaction mixture containing hydrolyzed OPs before
or after their separation by RPhC or TLC, 1 ml of 0.2%
trifluoroacetic acid and 2 ml of the matrix were added, and 1 ml
of the final mixture was spotted on the MALDI plate, air-dried,
and used for the analysis. Calibration of the MALDI spectra was
performed using the protein and OP standards I and II (Bruker
Daltonic, Germany) in the external and internal calibration mode.
Determination of the kinetic parameters
The reaction mixtures contained the standard components and
different concentrations of OPs. All measurements (initial rates)
were taken under the conditions of the pseudo-first order of the
reaction within the linear regions of the time courses(,40% of OP
hydrolysis). The cleavage products were analyzed by TLC. The
activity of IgGmixwas determined as a decrease in the percentage
of initial X-OPs converted to shorter X-OPs, corrected for the
distribution of the fluorescence label between these spots in the
control (incubation of X-OPs in the absence of Abs) and taking
into account the concentration of each OP in every reaction
mixture. The KM and Vmax (apparent kcat=Vmax/[Abs]) values
were calculated from the dependencies of V versus [OP] by least-
squares non-linear fitting using Microcal Origin v5.0 software and
presented as linear transformations using a Lineweaver–Burk plot
. Errors in the values were within 10–15%. The results are
reported as mean6S.E. of at least three independent experiments.
This research was made possible in part by grants from the Presidium of
the Russian Academy of Sciences (Molecular and Cellular Biology
Program, 6.7; Fundamental Sciences to Medicine, 5.13), Russian
Table 2. The data of RPhC, TLC, and MALDI analysis of molecular masses of fluorescent ligopeptides forming after incubation of X-
OP25 with sle-IgGmix.
Sites of cleavage of X-OP25 (OPs
found by massspectrometry in the
reaction mixture and peaks after
Mol. mass, Da
(ratio mass/charge, H+-form)
Peak number after
RPhC (Fig. 5A)
Relative content of
after a medium
hydrolysis of X-
0 X* 417.0417.2 1;C1** 1***
1 X- A 488.84489.0 1;2;C11;2(3)
2 X- AQ616.97 617.2 4;C14
3 X- AQG674.02 674.54 (6);C14(6)
4 X- AQGT775.13 775.26;7(3.4) C16;7(3;4) 16–20
5 X- AQGTL888.29888.44(9);C1 4(9)32–36
6X-AQGTLS 975.36975.5 2;3;C1 2;3Together 6–7; 6..7
7 X-AQGTLSK 1104.541104.62; C12
8 X-AQGTLSKI 1217.71218.08;9(1;2;3); C18;9(1;2;3)Together 13–17
9X-AQGTLSKIF1364.871364.96 (9);C16 (9)
12 X-AQGTLSKIFKLG1664.261664.5 3;6;C13;6
21X-AQGTLSKIFKLGGRD SRSGSP2565.18 2565.31;2; C1 1;2 Together 10–15
*Free fluorescent compound; all analyzed OPs contained fluorescent X-component.
**The same products of the hydrolysis separated by RPhC (Fig. 5A) were revealed in several peaks by MALDI spectrometry; the main peaks are marked in bold, while
additional peaks are shown in parentheses. C1 reflects the presence of signal corresponding to the analyzed product in the spectrum of total reaction mixture.
***The same several products of the hydrolysis corresponding to each peak after RPhC (Fig. 5A) were revealed not only by MALDI spectrometry, but also by TLC (Fig. 5B)
Multiple Sites of Myelin Basic Protein Cleavage
PLOS ONE | www.plosone.org12March 2013 | Volume 8 | Issue 3 | e51600
Foundation for Basic Research (10-04-00281), and funds from the Siberian
Division of the Russian Academy of Sciences.
Idea of study: GAN. Performed the experiments: AT PD LPK. Analyzed
the data: VNB GAN. Contributed reagents/materials/analysis tools: LPK
VNB. Wrote the paper: GAN.
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