2017
DOI: 10.3390/ijms18061192
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Conformational Flexibility Differentiates Naturally Occurring Bet v 1 Isoforms

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… Show more

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Cited by 19 publications
(20 citation statements)
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“…Similar buffer‐dependent oligomerization of Bet v 1 or homologous allergens from plants, eg Mal d 1 from apple, has been reported earlier, suggesting that the formulation of recombinant Bet v 1 preparations is critical when analysing and evaluating functional IgE interaction of recombinant allergen variants . In addition, the conformational stability of Bet v 1 variants might vary, as has been recently shown for Bet v 1.0102, which exhibits a higher conformational heterogeneity and flexibility than Bet v 1.0101 under neutral buffer conditions . Therefore, we assume that the observed reduced IgE‐binding capacity of Bet v 1.0102 (and probably of Bet v 1.0104) in Western blot/ELISA might be caused by a faster unfolding of these variants compared to Bet v 1.0101 upon contact or adhesion on surfaces.…”
Section: Discussionsupporting
confidence: 76%
“…Similar buffer‐dependent oligomerization of Bet v 1 or homologous allergens from plants, eg Mal d 1 from apple, has been reported earlier, suggesting that the formulation of recombinant Bet v 1 preparations is critical when analysing and evaluating functional IgE interaction of recombinant allergen variants . In addition, the conformational stability of Bet v 1 variants might vary, as has been recently shown for Bet v 1.0102, which exhibits a higher conformational heterogeneity and flexibility than Bet v 1.0101 under neutral buffer conditions . Therefore, we assume that the observed reduced IgE‐binding capacity of Bet v 1.0102 (and probably of Bet v 1.0104) in Western blot/ELISA might be caused by a faster unfolding of these variants compared to Bet v 1.0101 upon contact or adhesion on surfaces.…”
Section: Discussionsupporting
confidence: 76%
“…However, in describing the Bet v 1 variants as conformational ensembles we find a coherent link between local unfolding probability and proteolytic susceptibility. In many experimental and computational studies this relation has already been debated (Parsell and Sauer, 1989;Thai et al, 2004;Ohkuri et al, 2010;Asam et al, 2014;Grutsch et al, 2014Grutsch et al, , 2017Scheiblhofer et al, 2017). Yet, to the best of our knowledge, to this point no structural model of a partially unfolded state has been suggested.…”
Section: Discussionmentioning
confidence: 99%
“…With the use of NMR relaxation dispersion measurements, we found the initial cleavage site in Bet v 1 d to be more dynamic than in Bet v 1a, particularly on the millisecond timescale. Yet, all previous calculations were adjusted to the experimental conditions and thus protonation states resembling pH 7 were applied (Machado et al, 2016;Grutsch et al, 2017). In this study however, we aim at modeling ensembles of Bet v 1 variants, as they are expected to occur at pH 5.…”
Section: Introductionmentioning
confidence: 99%
“…No significant alterations regarding the secondary structural element composition due to ligand binding were observed [6••]. Changes in structural dynamics of Bet v 1 affect the accessibility of its proteolytic cleavage sites to lysosomal proteases leading to a reduction in cleavage efficiency and consequently affecting the availability of Bet v 1 peptides for optimal peptide presentation to T cells via the major histocompatibility complex class II (MHC-II) receptor [54,55]. Antigen presentation facilitated by antigen presenting cells is a necessary aspect for Th2 polarization, a key mechanism mandatory for the development of IgE-mediated allergic immune response.…”
Section: Influences On Physicochemical Properties and Proteolytic Promentioning
confidence: 99%