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Int. J. Mol. Sci. 2017, 18(6), 1192; doi:10.3390/ijms18061192

Conformational Flexibility Differentiates Naturally Occurring Bet v 1 Isoforms

1
Institute of Organic Chemistry & Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria
2
Institute of Inorganic and Theoretical Chemistry & Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria
These authors contributed equally to this work.
Current Address: Department of Medicinal Chemistry, Boehringer Ingelheim RCV GmbH & Co KG, Doktor-Boehringer-Gasse 5-11, A-1120 Vienna, Austria.
*
Authors to whom correspondence should be addressed.
Academic Editors: Fatima Ferreira and Hans Brandstetter
Received: 28 April 2017 / Revised: 25 May 2017 / Accepted: 30 May 2017 / Published: 3 June 2017
(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)
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Abstract

The protein Bet v 1 represents the main cause for allergic reactions to birch pollen in Europe and North America. Structurally homologous isoforms of Bet v 1 can have different properties regarding allergic sensitization and Th2 polarization, most likely due to differential susceptibility to proteolytic cleavage. Using NMR relaxation experiments and molecular dynamics simulations, we demonstrate that the initial proteolytic cleavage sites in two naturally occurring Bet v 1 isoforms, Bet v 1.0101 (Bet v 1a) and Bet v 1.0102 (Bet v 1d), are conformationally flexible. Inaccessible cleavage sites in helices and strands are highly flexible on the microsecond-millisecond time scale, whereas those located in loops display faster nanosecond-microsecond flexibility. The data consistently show that Bet v 1.0102 is more flexible and conformationally heterogeneous than Bet v 1.0101. Moreover, NMR hydrogen-deuterium exchange measurements reveal that the backbone amides in Bet v 1.0102 are significantly more solvent exposed, in agreement with this isoform’s higher susceptibility to proteolytic cleavage. The differential conformational flexibility of Bet v 1 isoforms, along with the transient exposure of inaccessible sites to the protein surface, may be linked to proteolytic susceptibility, representing a potential structure-based rationale for the observed differences in Th2 polarization and allergic sensitization. View Full-Text
Keywords: allergens; proteolytic processing; allergic sensitization; allergen structure; flexibility allergens; proteolytic processing; allergic sensitization; allergen structure; flexibility
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MDPI and ACS Style

Grutsch, S.; Fuchs, J.E.; Ahammer, L.; Kamenik, A.S.; Liedl, K.R.; Tollinger, M. Conformational Flexibility Differentiates Naturally Occurring Bet v 1 Isoforms. Int. J. Mol. Sci. 2017, 18, 1192.

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