Conformational Flexibility Differentiates Naturally Occurring Bet v 1 Isoforms

Grutsch, Sarina; Fuchs, Julian E.; Ahammer, Linda; Kamenik, Anna S.; Liedl, Klaus R.; Tollinger, Martin

doi:10.3390/ijms18061192

Cited by 19 publications

(20 citation statements)

References 55 publications

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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%

Quality and potency profile of eight recombinant isoallergens, largely mimicking total Bet v 1‐specific IgE binding of birch pollen

Loetzen

Reuter

Spiric

et al. 2019

Clin Experimental Allergy

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Section: Discussionsupporting

confidence: 76%

Quality and potency profile of eight recombinant isoallergens, largely mimicking total Bet v 1‐specific IgE binding of birch pollen

Loetzen

Reuter

Spiric

et al. 2019

Clin Experimental Allergy

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“…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%

Dynamics Rationalize Proteolytic Susceptibility of the Major Birch Pollen Allergen Bet v 1

Kamenik

Hofer

Handle

et al. 2020

Front. Mol. Biosci.

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Proteolytic susceptibility during endolysosomal degradation is decisive for allergic sensitization. In the major birch pollen allergen Bet v 1 most protease cleavage sites are located within its secondary structure elements, which are inherently inaccessible to proteases. The allergen thus must unfold locally, exposing the cleavage sites to become susceptible to proteolysis. Hence, allergen cleavage rates are presumed to be linked to their fold stability, i.e., unfolding probability. Yet, these locally unfolded structures have neither been captured in experiment nor simulation due to limitations in resolution and sampling time, respectively. Here, we perform classic and enhanced molecular dynamics (MD) simulations to quantify fold dynamics on extended timescales of Bet v 1a and two variants with higher and lower cleavage rates. Already at the nanosecond-timescale we observe a significantly higher flexibility for the destabilized variant compared to Bet v 1a and the proteolytically stabilized mutant. Estimating the thermodynamics and kinetics of local unfolding around an initial cleavage site, we find that the Bet v 1 variant with the highest cleavage rate also shows the highest probability for local unfolding. For the stabilized mutant on the other hand we only find minimal unfolding probability. These results strengthen the link between the conformational dynamics of allergen proteins and their stability during endolysosomal degradation. The presented approach further allows atomistic insights in the conformational ensemble of allergen proteins and provides probability estimates below experimental detection limits.

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“…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%

Ligand Binding of PR-10 Proteins with a Particular Focus on the Bet v 1 Allergen Family

Aglas

Soh

Kraiem

et al. 2020

Curr Allergy Asthma Rep

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Purpose of Review Pathogenesis-related class 10 (PR-10) proteins are highly conserved plant proteins, which are induced in response to abiotic and biotic stress factors. To date, no unique biological function could be assigned to them. Rather a more general role of PR-10 in plant development and defense mechanisms has been proposed. In addition, some PR-10 proteins act as allergens by triggering allergic symptoms in sensitized individuals. Regardless of the diversity of reported activities, all PR-10 proteins share a common fold characterized by a solvent-accessible hydrophobic cavity, which serves as a binding site for a myriad of small-molecule ligands, mostly phytohormones and flavonoids. Recent Findings Most of available data relate to the ligand binding activity of allergenic PR-10, particularly for those belonging to Bet v 1 family of allergens. Bet v 1 and its homologues were shown to bind flavonoids with high affinity, but the specificity appears to differ between homologues from different species. The flavonoid Q3O-(Glc)-Gal was shown to specifically bind to hazelnut Cor a 1 but not to Bet v 1. Similarly, Q3OS bound only to the major isoform Bet v 1.0101 and not to other closely related isoforms. In contrast, Bet v 1 and hazelnut Cor a 1 showed very similar binding behavior towards other flavonoids such as quercetin, genistein, apigenin, daidzein, and resveratrol. Summary Recent research findings highlighted the importance of more precise knowledge of ligand binding for understanding the functional diversification of PR-10 proteins.

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Conformational Flexibility Differentiates Naturally Occurring Bet v 1 Isoforms

Cited by 19 publications

References 55 publications

Quality and potency profile of eight recombinant isoallergens, largely mimicking total Bet v 1‐specific IgE binding of birch pollen

Quality and potency profile of eight recombinant isoallergens, largely mimicking total Bet v 1‐specific IgE binding of birch pollen

Dynamics Rationalize Proteolytic Susceptibility of the Major Birch Pollen Allergen Bet v 1

Ligand Binding of PR-10 Proteins with a Particular Focus on the Bet v 1 Allergen Family

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