Biology subjects

Berndt, S.

Publications and source records attributed to Berndt, S..

6 recordsLinked to original sources

bioRxiv2026

The isolated Stachel peptide of the adhesion G protein-coupled receptor GPR126 is intrinsically disordered

Several members of the adhesion subfamily of G protein-coupled receptors (aGPCRs) are capable of self-activation by an internal agonist sequence (aka the Stachel) thats exposed upon removal or conformational changes of the N-terminal fragment of the receptor. Synthetic peptides derived from the Stachel sequence can be used as exogenous agonists. In the inactive form, the Stachel is sequestered as the {beta}13-strand within the GPCR Autoproteolysis-INducing (GAIN) domain, but it engages the seven transmembrane region as a helix when it is either an intramolecular sequence or a synthetic peptide. Little is known about the molecular details underlying this transition, but we hypothesize that a disordered conformation is central to this intermediate state in receptor activation. Despite the primarily helical Stachel AlphaFold3 and Pepfold4 models predicted with high confidence for the entire aGPCR subfamily, disorder predictions and biophysical experiments reveal a predominantly disordered conformation in solution. Investigating the ADGRG6/GPR126 Stachel peptide, circular dichroism (CD) and nuclear magnetic resonance (NMR) experiments reveal a predominantly random coil conformation in aqueous buffer, polar detergent micelles, and zwitterionic lipids. Titration of trifluoroethanol uncovered a two-state equilibrium between an unfolded and helix-containing conformation with NMR localizing a single-turn helix to residues L846-L849. Taken together, these data indicate the ADGRG6/GPR126 Stachel peptide is primarily disordered, but small populations may adopt a helix-containing conformer that seems to support a conformational-selection activation mechanism.

biophysics↗

bioRxiv2025

Reversing Nicotine Toxicity: how Platelet-Rich Plasma Enhances Cell Recovery through Autophagy Modulation

BackgroundChronic exposure to nicotine significantly exacerbates periodontitis, a prevalent inflammatory disease, by inducing cellular processes such as autophagy and inflammation in gingival fibroblasts. Current therapies often fail to fully address these cellular alterations in smokers, highlighting a need for innovative therapeutic and generative approaches. ObjectiveThis study explores the therapeutic potential of Platelet-Rich Plasma (PRP), a blood-derived product, to modulate nicotine-induced biological activities in primary gingival fibroblasts. It aims at understanding the underlying cellular mechanisms and assessing the efficacy of PRP as an adjunct treatment for periodontitis in smokers. MethodsGingival fibroblasts were treated with increasing concentrations of nicotine, which led to senescence and autophagy. Subsequent treatment with autologous PRP was evaluated for its effect on the reversion of these processes, by measuring cell migration and proliferation, metabolic activity, as well as by looking at senescence and autophagic markers. A Caenorhabditis elegans model of autophagy was used to assess nicotine and PRP biological activities in an in vivo environment. ResultsNicotine at high concentrations triggered cellular vacuolization, a decrease in metabolism, viability and proliferation that was partially (with 500 ng/ml nicotine) or completely (with 250 ng/ml nicotine) reversed by a concomitant treatment with 10% PRP. Nicotine alone (250 ng/ml) slightly enhanced migration, while concomitant treatment between nicotine and PRP significantly increased their migration potential. In Caenorhabditis elegans, PRP reduced the nicotine-induced autophagic activity, as evidenced by decreased numbers of autophagosome and a higher number of viable worms during adulthood in comparison to nicotine control conditions. A screening of gingival fibroblast secretome revealed a modulation of autophagy-related cytokines in response to nicotine and/or PRP. ConclusionThe findings demonstrate that PRP could effectively inhibit nicotine-induced autophagy gingival fibroblasts, offering insights into its possible use as a therapeutic tool for managing periodontitis in smokers. The study underscores the potential of PRP in altering disease progression by modulating key cellular processes affected by smoking.

cell biology↗

bioRxiv2022

FORGEdb: systematic analysis of candidate causal variants to uncover target genes and mechanisms in complex traits.

The majority of disease-associated variants identified through genome-wide association studies (GWAS) are located outside of protein-coding regions and are overrepresented in sequences that regulate gene expression. Prioritizing candidate regulatory variants and potential biological mechanisms for further functional experiments, such as genome editing, can be challenging, especially in regions with a high number of variants in strong linkage disequilibrium or multiple proximal gene targets. Improved annotation of the regulatory genome can help identify promising variants and target genes for functional genomics experiments. To advance this area, we developed FORGEdb (https://forge2.altiusinstitute.org/files/forgedb.html), a web-based tool that can rapidly integrate data for individual genetic variants, providing information on associated regulatory elements, transcription factor (TF) binding sites and target genes for over 37 million variants. FORGEdb uses annotations derived from data across a wide range of biological samples to delineate the regulatory context for each variant at the cell type level. Multiple data types, such as Combined Annotation Dependent Depletion (CADD) scores, expression quantitative trait loci (eQTLs), activity-by-contact (ABC) interactions, Contextual Analysis of TF Occupancy (CATO) scores, transcription factor (TF) motifs, DNase I hotspots, histone mark ChIP-seq peaks and chromatin states, are included in FORGEdb and these annotations are integrated into a FORGEdb score to guide assessment of functional importance. In summary, FORGEdb provides an expansive and unique resource of genomic annotations and an integrated score that can be used to accelerate the translation of identified genetic loci into biological insight.

genomics↗

bioRxiv2021

Mimicking extracellular matrix-mediated mechano-activation by antibodies to control signaling of the adhesion G protein-coupled receptor GPR126/ADGRG6

The adhesion G protein-coupled receptor (aGPCR) GPR126/ADGRG6 plays an important role in several physiological functions, such as myelination or peripheral nerve repair. This renders the receptor an attractive pharmacological target. GPR126 is a mechano-sensor that translates binding of extracellular matrix (ECM) molecules to its N terminus into a metabotropic intracellular signal. To date, the structural requirements and the character of the forces needed for this ECM-mediated receptor activation are largely unknown. In this study we provide this information by combining classic second messenger detection with single cell atomic force microscopy. We establish a monoclonal antibody targeting the N terminus to stimulate GPR126 and compare it to the activation through its known ECM ligands collagen IV and laminin 211. As each ligand uses a distinct mode of action, the N terminus can be viewed as an allosteric module that can fine-tune receptor activation in a context-specific manner.

molecular biology↗

bioRxiv2018

The role of glycaemic, lipid, blood pressure and obesity risk factors as mediators of the effect of height on Coronary Artery Disease and Type 2 Diabetes Mellitus: A Mendelian Randomisation Study.

We investigated by Mendelian Randomisation (MR) analyses the causal effect of adult height on coronary artery disease (CAD) (23,755 cases, 425,339 controls) and type 2 diabetes (T2D) (29,427 cases, 416,908 controls) in UK Biobank. We then examined whether such effects are mediated via known cardiometabolic risk factors including body mass index (BMI), glycaemic traits, lipid levels and blood pressure. We further cross-checked our findings by two-sample MR and Multivariate MR analyses with publicly available summary statistics data. One standard deviation (SD) higher genetically determined height (~6.5 cm) was causally associated with a 14% decrease in CAD risk (OR= 0.86, 95% CI= 0.790.94). This causal association remained significant after performing sensitivity analyses relaxing pleiotropy assumptions. The causal effect of height on CAD risk appeared to be independent of risk factors such as lipid levels, blood pressure and BMI; association was reduced by only 1-3% after adjustment for potential mediators. We observed no direct causal effect of height on T2D risk, once its effect on BMI was taken into account (OR= 0.99, 95% CI= 0.96-1.02), suggesting that BMI acts as a mediator.

genetics↗

bioRxiv2018

Shared heritability and functional enrichment across six solid cancers

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg=0.57, p=4.6x10-8), breast and ovarian cancer (rg=0.24, p=7x10-5), breast and lung cancer (rg=0.18, p=1.5x10-6) and breast and colorectal cancer (rg=0.15, p=1.1x10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

genomics↗