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Papers In Press, published online ahead of print September 24, 2002
Departments of Chemistry and Chemical Engineering, Stanford University, Stanford, CA 94305-5025
Corresponding Author: ck{at}chemeng.stanford.edu
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 MHC 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.
J. Biol. Chem, 10.1074/jbc.M207606200
Submitted on July 29, 2002
Revised on September 23, 2002
Accepted on September 24, 2002
Circular dichroism and nuclear magnetic resonance spectroscopic analysis of immunogenic gluten peptides and their analogs
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