Molecular and in vivo studies of a glutamate-class prolyl-endopeptidase for coeliac disease therapy

Laura Amo-Maestro, Soraia R. Mendes, Arturo Rodríguez-Banqueri, Laura Garzon-Flores, Marina Girbal, María José Rodríguez-Lagunas, Tibisay Guevara, Àngels Franch, Francisco J. Pérez-Cano, Ulrich Eckhard and F. Xavier Gomis-Rüth ()
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Laura Amo-Maestro: Molecular Biology Institute of Barcelona (CSIC)
Soraia R. Mendes: Molecular Biology Institute of Barcelona (CSIC)
Arturo Rodríguez-Banqueri: Molecular Biology Institute of Barcelona (CSIC)
Laura Garzon-Flores: Molecular Biology Institute of Barcelona (CSIC)
Marina Girbal: University of Barcelona
María José Rodríguez-Lagunas: University of Barcelona
Tibisay Guevara: Molecular Biology Institute of Barcelona (CSIC)
Àngels Franch: University of Barcelona
Francisco J. Pérez-Cano: University of Barcelona
Ulrich Eckhard: Molecular Biology Institute of Barcelona (CSIC)
F. Xavier Gomis-Rüth: Molecular Biology Institute of Barcelona (CSIC)

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract The digestion of gluten generates toxic peptides, among which a highly immunogenic proline-rich 33-mer from wheat α-gliadin, that trigger coeliac disease. Neprosin from the pitcher plant is a reported prolyl endopeptidase. Here, we produce recombinant neprosin and its mutants, and find that full-length neprosin is a zymogen, which is self-activated at gastric pH by the release of an all-β pro-domain via a pH-switch mechanism featuring a lysine plug. The catalytic domain is an atypical 7+8-stranded β-sandwich with an extended active-site cleft containing an unprecedented pair of catalytic glutamates. Neprosin efficiently degrades both gliadin and the 33-mer in vitro under gastric conditions and is reversibly inactivated at pH > 5. Moreover, co-administration of gliadin and the neprosin zymogen at the ratio 500:1 reduces the abundance of the 33-mer in the small intestine of mice by up to 90%. Neprosin therefore founds a family of eukaryotic glutamate endopeptidases that fulfils requisites for a therapeutic glutenase.

Date: 2022
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DOI: 10.1038/s41467-022-32215-1

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