scholarly journals The use of 4,4,4-trifluorothreonine to stabilize extended peptide structures and mimic β-strands

2017 ◽  
Vol 13 ◽  
pp. 2842-2853 ◽  
Author(s):  
Yaochun Xu ◽  
Isabelle Correia ◽  
Tap Ha-Duong ◽  
Nadjib Kihal ◽  
Jean-Louis Soulier ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Amyloid Peptide ◽  
Central Position ◽  
Aggregation Process ◽  
Proof Of Concept ◽  
Protein Protein Interactions ◽  
Conformational Studies ◽  
Dynamics Simulations ◽  
Β Sheet ◽  
Central Residue

Pentapeptides having the sequence R-HN-Ala-Val-X-Val-Leu-OMe, where the central residue X is L-serine, L-threonine, (2S,3R)-L-CF3-threonine and (2S,3S)-L-CF3-threonine were prepared. The capacity of (2S,3S)- and (2S,3R)-CF3-threonine analogues to stabilize an extended structure when introduced in the central position of pentapeptides is demonstrated by NMR conformational studies and molecular dynamics simulations. CF3-threonine containing pentapeptides are more prone to mimic β-strands than their natural Ser and Thr pentapeptide analogues. The proof of concept that these fluorinated β-strand mimics are able to disrupt protein–protein interactions involving β-sheet structures is provided. The CF3-threonine containing pentapeptides interact with the amyloid peptide Aβ1-42 in order to reduce the protein–protein interactions mediating its aggregation process.

scholarly journals Molecular dynamics shows complex interplay and long-range effects of post-translational modifications in yeast protein interactions

2021 ◽  
Vol 17 (5) ◽  
pp. e1008988
Author(s):  
Nikolina ŠoŠtarić ◽  
Vera van Noort
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Protein Structures ◽  
Cellular Protein ◽  
Free Energy Calculations ◽  
Protein Protein Interactions ◽  
Post Translational Modifications ◽  
Protein Properties ◽  
Dynamics Simulations

Post-translational modifications (PTMs) play a vital, yet often overlooked role in the living cells through modulation of protein properties, such as localization and affinity towards their interactors, thereby enabling quick adaptation to changing environmental conditions. We have previously benchmarked a computational framework for the prediction of PTMs’ effects on the stability of protein-protein interactions, which has molecular dynamics simulations followed by free energy calculations at its core. In the present work, we apply this framework to publicly available data on Saccharomyces cerevisiae protein structures and PTM sites, identified in both normal and stress conditions. We predict proteome-wide effects of acetylations and phosphorylations on protein-protein interactions and find that acetylations more frequently have locally stabilizing roles in protein interactions, while the opposite is true for phosphorylations. However, the overall impact of PTMs on protein-protein interactions is more complex than a simple sum of local changes caused by the introduction of PTMs and adds to our understanding of PTM cross-talk. We further use the obtained data to calculate the conformational changes brought about by PTMs. Finally, conservation of the analyzed PTM residues in orthologues shows that some predictions for yeast proteins will be mirrored to other organisms, including human. This work, therefore, contributes to our overall understanding of the modulation of the cellular protein interaction networks in yeast and beyond.

scholarly journals β-Hairpin mimics containing a piperidine–pyrrolidine scaffold modulate the β-amyloid aggregation process preserving the monomer species

2017 ◽  
Vol 8 (2) ◽  
pp. 1295-1302 ◽  
Author(s):  
S. Pellegrino ◽  
N. Tonali ◽  
E. Erba ◽  
J. Kaffy ◽  
M. Taverna ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Peptide Aggregation ◽  
Aggregation Process ◽  
Amyloid Aggregation ◽  
Protein Protein Interactions ◽  
Β Amyloid

Acyclic β-hairpins designed on oligomeric and fibril structures of Aβ1–42 disrupt protein–protein interactions mediating amyloid β-peptide aggregation.

scholarly journals Selective Affimers Recognize BCL-2 Family Proteins Through Non-Canonical Structural Motifs

2019 ◽  
Author(s):  
Jennifer A. Miles ◽  
Fruzsina Hobor ◽  
James Taylor ◽  
Christian Tiede ◽  
Philip R. Rowell ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Cell Biology ◽  
Competitive Inhibition ◽  
Antibody Binding ◽  
Proof Of Concept ◽  
Protein Protein Interactions ◽  
The Family ◽  
Selective Ligands ◽  
Binding Cleft ◽  
Characterisation Methods

AbstractThe BCL-2 family is a challenging set of proteins to target selectively due to sequence and structural homologies across the family. Selective ligands for the BCL-2 family regulators of apoptosis are desirable as probes to understand cell biology and apoptotic signalling pathways, and as starting points for inhibitor design. We have used phage display to isolate Affimer reagents (non-antibody binding proteins based on a conserved scaffold) to identify ligands for MCL-1, BCL-xL, BCL-2, BAK and BAX, then used multiple biophysical characterisation methods to probe the interactions. We established that purified Affimers elicit selective and potent recognition of their target BCL-2 protein. For anti-apoptotic targets, competitive inhibition of their canonical protein-protein interactions is demonstrated. Co-crystal structures reveal an unprecedented mode of molecular recognition; where a BH3 helix is normally bound, flexible loops from the Affimer dock into the BH3 binding cleft. Moreover, the Affimers induce a change in the target proteins towards a desirable drug bound like conformation. These results indicate Affimers can be used as alternative templates to inspire design of selective BCL-2 family modulators, and provide proof-of-concept for the elaboration of selective non-antibody binding reagents for use in cell-biology applications.

scholarly journals Structural and Functional Basis of Red Palm Weevil: Pathogen Interactions Leading Towards Enhanced Crop Production in Date Palms

2021 ◽  
Author(s):  
Meshari Alazmi ◽  
Nawaf Alshammari ◽  
Naimah A. Alanazi ◽  
Abdel Moneim E. Sulieman
Keyword(s):  
Protein Interactions ◽  
Crop Production ◽  
Agricultural Research ◽  
Plant Diseases ◽  
Health Production ◽  
Protein Protein Interactions ◽  
Functional Basis ◽  
Root Cause ◽  
Pathogen Protein ◽  
Dynamics Simulations

Abstract Food safety remains a significant challenge despite the growth and development in agricultural research and the advent of modern biotechnological and agricultural tools. Though the agriculturist struggles to aid the growing population's needs, many pathogen-based plant diseases by their direct impact on cell division and tissue development have led to the loss of tons of food crops every year. Though there are many conventional and traditional methods to overcome this issue, the amount and time spend are huge. Scientists have developed systems biology tools to study the root cause of the problem and rectify it. Host-pathogen protein interactions (HPIs) have a promising role in identifying the pathogens' strategy to conquer the host organism. In this paper, the interactions between the host Rhynchophorus ferrugineus (an invasive wood-boring pest that destroys palm) and the pathogens Proteus mirabilis, Serratia marcescens, and Klebsiella pneumoniae are comprehensively studied using protein-protein interactions, molecular docking, and followed by 200 ns molecular dynamics simulations. This study elucidates the structural and functional basis of these proteins leading towards better plant health, production, and reliability.

scholarly journals Insights into the Role of Membrane Lipids in the Structure, Function and Regulation of Integral Membrane Proteins

2021 ◽  
Vol 22 (16) ◽  
pp. 9026
Author(s):  
Kenta Renard ◽  
Bernadette Byrne
Keyword(s):  
Membrane Proteins ◽  
Membrane Protein ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Membrane Lipids ◽  
Protein Protein Interactions ◽  
Technological Advances ◽  
Highly Hydrophobic ◽  
Dynamics Simulations ◽  
And Function

Membrane proteins exist within the highly hydrophobic membranes surrounding cells and organelles, playing key roles in cellular function. It is becoming increasingly clear that the membrane does not just act as an appropriate environment for these proteins, but that the lipids that make up these membranes are essential for membrane protein structure and function. Recent technological advances in cryogenic electron microscopy and in advanced mass spectrometry methods, as well as the development of alternative membrane mimetic systems, have allowed experimental study of membrane protein–lipid complexes. These have been complemented by computational approaches, exploiting the ability of Molecular Dynamics simulations to allow exploration of membrane protein conformational changes in membranes with a defined lipid content. These studies have revealed the importance of lipids in stabilising the oligomeric forms of membrane proteins, mediating protein–protein interactions, maintaining a specific conformational state of a membrane protein and activity. Here we review some of the key recent advances in the field of membrane protein–lipid studies, with major emphasis on respiratory complexes, transporters, channels and G-protein coupled receptors.

Evolutionary selection for protein aggregation

2012 ◽  
Vol 40 (5) ◽  
pp. 1032-1037 ◽  
Author(s):  
Natalia Sanchez de Groot ◽  
Marc Torrent ◽  
Anna Villar-Piqué ◽  
Benjamin Lang ◽  
Salvador Ventura ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Protein Interactions ◽  
Current Knowledge ◽  
Protein Aggregates ◽  
Cellular Systems ◽  
Aggregation Process ◽  
Loss Of Function ◽  
Protein Protein Interactions ◽  
Wide Range ◽  
Range Of Functions

Protein aggregation is being found to be associated with an increasing number of human diseases. Aggregation can lead to a loss of function (lack of active protein) or to a toxic gain of function (cytotoxicity associated with protein aggregates). Although potentially harmful, protein sequences predisposed to aggregation seem to be ubiquitous in all kingdoms of life, which suggests an evolutionary advantage to having such segments in polypeptide sequences. In fact, aggregation-prone segments are essential for protein folding and for mediating certain protein–protein interactions. Moreover, cells use protein aggregates for a wide range of functions. Against this background, life has adapted to tolerate the presence of potentially dangerous aggregation-prone sequences by constraining and counteracting the aggregation process. In the present review, we summarize the current knowledge of the advantages associated with aggregation-prone stretches in proteomes and the strategies that cellular systems have developed to control the aggregation process.

scholarly journals Multiple Dimerizing Motifs Modulate the Dimerization of the Syndecan Transmembrane Domains

2020 ◽  
Author(s):  
J. Chen ◽  
F. Wang ◽  
C. He ◽  
S-Z. Luo
Keyword(s):  
Protein Interactions ◽  
Self Assembly ◽  
Transmembrane Domains ◽  
Integral Membrane Proteins ◽  
Sequence Motifs ◽  
Protein Protein Interactions ◽  
Dynamics Simulations ◽  
Considerable Complexity ◽  
Shed Light ◽  
Common Sequence

AbstractSyndecans(SDCs) are a family of four members of integral membrane proteins, which play important roles in cell-cell interactions. Dimerization/oligomerization generated by transmembrane domains (TMDs) appear to crucially regulate several functional behaviors of all syndecan members. The distinct hierarchy of protein-protein interactions mediated by the syndecan TMDs may give rise to considerable complexity in the functions of syndecans. The molecular mechanism of the different dimerization tendencies in each type of SDCs remains unclear. Here, the self-assembly process of syndecan TMD homodimers and heterodimers was studied in molecular details by molecular dynamics simulations. Our computational results showed that the SDC2 forms the most stable homodimer while the SDC1 TMD dimerizes weakly, which is consistent with previous experimental results. Detailed analysis suggests that instead of the conserved dimerizing motif G8XXXG12 in all four SDCs involved in homo- and hetero-dimerization of SDCs, the G3XXXA7 motif in SDC1 competes with the interface of G8XXXG12 and thus disturbs the SDC1 involved dimerization. The SDC3 which contains a G9XXXA13 motif, however, forms a more stable dimer than SDC1, indicating the complexity of the competing effect of the GXXXA motif. As GXXXG and GXXXA are two common sequence motifs in the dimerization of helices, our results shed light on the competing effect of multiple dimerizing motifs on the dimerization of transmembrane domains.

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