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J. Biol. Chem., Vol. 277, Issue 47, 45572-45578, November 22, 2002
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§,, and¶
**
From the Departments of Celiac Sprue, or gluten-sensitive enteropathy, is
an inheritable human disease of the small intestine that is triggered
by the dietary intake of gluten. Recently, several Pro- and Gln-rich peptide sequences (most notably PQPQLPY and analogs) have been identified from gluten with potent immunogenic activity toward CD4+ T cells from small intestinal biopsies of Celiac
Sprue patients. These peptides have three unusual properties. First,
they are relatively stable toward further proteolysis by gastric,
pancreatic, and intestinal enzymes. Second, they are recognized and
deamidated by human tissue transglutaminase (tTGase) with high
selectivity. Third, tTGase-catalyzed deamidation enhances their
affinity for HLA-DQ2, the disease-specific class II major
histocompatibility complex heterodimer. In an attempt to seek a
mechanistic explanation for these properties, we undertook secondary
structural studies on PQPQLPY and its analogs. Circular dichroism
studies on a series of monomeric and dimeric analogs revealed a strong
polyproline II helical propensity in a subset of them. Two-dimensional
nuclear magnetic resonance spectroscopic analysis confirmed a
polyproline II conformation of PQPQLPY, and was also used to elucidate
the secondary structure of the most helical variant,
(D-P)QPQLPY. Remarkably, a strong correlation was observed
between polyproline II content of naturally occurring gluten peptides
and the specificity of human tTGase toward these substrates. Analogs
with up to two D-amino acid residues retained both
polyproline II helical content and transglutaminase affinity. Since the
Michaelis constant (Km) is the principal
determinant of tTGase specificity for naturally occurring gluten
peptides and their analogs, our results suggest that the tTGase binding
site may have a preference for polyproline II helical substrates. If
so, these insights could be exploited for the design of selective small
molecule inhibitors of this pharmacologically important enzyme.
Chemical Engineering,
¶ Chemistry, and Biochemistry, Stanford University,
Stanford, California 94305-5025
The on-line version of this article (available at
http://www.jbc.org) contains supplementary Tables S1 and S2 and
supplementary Figs. S1-S4).
§
Recipient of a postdoctoral fellowship from the Fondation pour la
Recherche Médicale (France).
**
To whom correspondence should be addressed: Depts. Of Chemical
Engineering, Chemistry, and Biochemistry, Stanford University, Stanford, CA 94305-5025. Tel./Fax: 650-723-6538; E-mail:
ck@chemeng.stanford.edu.
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