134 research outputs found
INITIAL INSIGHTS INTO THE STRUCTURE-ACTIVITY RELATIONSHIPS OF AVIAN DEFENSINS.
Numerous β-defensins have been identified in birds and the potential use of these peptides as alternatives to antibiotics has been proposed, in particular to fight antibiotic-resistant and zoonotic bacterial species. Little is known about the mechanism of antibacterial activity of avian β-defensins (AvBDs), and the present work was carried out to obtain initial insights into the involvement of structural features or specific residues in the antimicrobial activity of chicken AvBD2. Chicken AvBD2 and its enantiomeric counterpart were chemically synthesized. Peptide elongation and oxidative folding were both optimized. The similar antimicrobial activity measured for both L- and D- proteins clearly indicates that there is no chiral partner. Therefore the bacterial membrane is in all likelihood the primary target. Moreover, this work evidences that the three-dimensional fold is required for an optimal antimicrobial activity, in particular for Gram-positive bacterial strains. The three-dimensional NMR structure of chicken AvBD2 defensin displays the structural 3-stranded antiparallel β-sheet characteristic of β-defensins. The surface of the molecule does not display any amphipathic character. In light of this new structure and of the king penguin AvBD103b defensin structure, the consensus sequence of avian β-defensin's family was analyzed. Well conserved residues were highlighted and the potential strategic role of the lysine 31 residue of AvBD2 emphasized. The synthetic AvBD2-K31A variant displayed substantial N-terminal structural modifications and a dramatic decrease in activity. Taken together, these results demonstrate the structural as well as the functional role of the critical lysine 31 residue in antimicrobial activity
Activation of TRPV2 and BKCa channels by the LL-37 enantiomers stimulates calcium entry and migration of cancer cells.
International audienceExpression of the antimicrobial peptide hCAP18/LL-37 is associated to malignancy in various cancer forms, stimulating cell migration and metastasis. We report that LL-37 induces migration of three cancer cell lines by activating the TRPV2 calcium-permeable channel and recruiting it to pseudopodia through activation of the PI3K/AKT pathway. Ca2+ entry through TRPV2 cooperated with a K+ efflux through the BKCa channel. In a panel of human breast tumors, the expression of TRPV2 and LL-37 was found to be positively correlated. The D-enantiomer of LL-37 showed identical effects as the L-peptide, suggesting that no binding to a specific receptor was involved. LL-37 attached to caveolae and pseudopodia membranes and decreased membrane fluidity, suggesting that a modification of the physical properties of the lipid membrane bilayer was the underlying mechanism of its effects
Dynamic Regulation of Tgf-B Signaling by Tif1Îł: A Computational Approach
TIF1Îł (Transcriptional Intermediary Factor 1 Îł) has been implicated in
Smad-dependent signaling by Transforming Growth Factor beta (TGF-β).
Paradoxically, TIF1Îł functions both as a transcriptional repressor or as an
alternative transcription factor that promotes TGF-β signaling. Using
ordinary differential-equation models, we have investigated the effect of
TIF1γ on the dynamics of TGF-β signaling. An integrative model that
includes the formation of transient TIF1Îł-Smad2-Smad4 ternary complexes is
the only one that can account for TGF-β signaling compatible with the
different observations reported for TIF1Îł. In addition, our model predicts
that varying TIF1Îł/Smad4 ratios play a critical role in the modulation of
the transcriptional signal induced by TGF-β, especially for short
stimulation times that mediate higher threshold responses. Chromatin
immunoprecipitation analyses and quantification of the expression of TGF-β
target genes as a function TIF1Îł/Smad4 ratios fully validate this
hypothesis. Our integrative model, which successfully unifies the seemingly
opposite roles of TIF1Îł, also reveals how changing TIF1Îł/Smad4 ratios
affect the cellular response to stimulation by TGF-β, accounting for a
highly graded determination of cell fate
A chemical toolbox for simplifying chemical protein synthesis
National audienc
Séminaire invité : Development of a molecular toolbox to simplify the chemical synthesis of proteins and constrained peptides natural products
International audienc
Séminaire invité : Development of a molecular toolbox to simplify the chemical synthesis of proteins and constrained peptides natural products
International audienc
Séminaire invité : Development of a molecular toolbox to simplify the chemical synthesis of proteins
National audienc
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