AI Article Synopsis
- The protein α-synuclein (αSN) has significant functions in the nervous system, and its interactions with lipid membranes are linked to diseases like Parkinson's.
- Research using TRESI-HDX-MS has revealed that αSN behaves differently depending on the lipid composition of membrane mimics, showing rapid changes with some lipids and more substantial changes with those promoting amyloid formation.
- Specific regions of the αSN sequence (residues 19-28 and 45-57) are affected by interactions with these amyloidogenic lipids, which supports the "broken-helix" model of αSN/membrane interactions but does not confirm the presence of a "helical extension" that could contribute to αSN aggregation.
Article Abstract
Both normal and pathological functions of α-synuclein (αSN), an abundant protein in the central and peripheral nervous system, have been linked to its interaction with membrane lipid bilayers. The ability to characterize structural transitions of αSN upon membrane complexation will clarify molecular mechanisms associated with αSN-linked pathologies, including Parkinson's disease (PD), multiple systems atrophy, and other synucleinopathies. In this work, time-resolved electrospray ionization hydrogen/deuterium exchange mass spectrometry (TRESI-HDX-MS) was employed to acquire a detailed picture of αSN's conformational transitions as it undergoes complexation with nanodisc membrane mimics with different headgroup charges (zwitterionic DMPC and negative POPG). Using this approach, αSN interactions with DMPC nanodiscs were shown to be rapid exchanging and to have little impact on the αSN conformational ensemble. Interactions with nanodiscs containing lipids known to promote amyloidogenesis (e.g., POPG), on the other hand, were observed to induce substantial and specific changes in the αSN conformational ensemble. Ultimately, we identify a region corresponding residues 19-28 and 45-57 of the αSN sequence that is uniquely impacted by interactions with "amyloidogenic" lipid membranes, supporting the existing "broken-helix" model for α-synuclein/membrane interactions, but do not detect a "helical extension" that is also thought to play a role in αSN aggregation.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/jasms.0c00463 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Three-step click assembly using trivalent platforms bearing azido, ethynyl, and fluorosulfonyl groups.
Chem Commun (Camb)
January 2025
Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku Tokyo 125-8585, Japan.
Divergent synthesis of triazoles was achieved using newly designed platform molecules possessing azide, alkyne, and fluorosulfonyl moieties. Consecutive conjugations by the sulfur(VI) fluoride exchange and following consecutive triazole formations allowed us to prepare a wide variety of bis(triazole)s by virtue of selective transformations. One-pot triple-click assembly of easily accessible modules led to the facile synthesis of middle-molecular-weight triazoles with various functional moieties.
View Article and Find Full Text PDFTuning Hydrogen Binding on Ru Sites by Ni Alloying on MoO Enables Efficient Alkaline Hydrogen Evolution for Anion Exchange Membrane Water Electrolysis.
Adv Sci (Weinh)
January 2025
Division of Chemical and Material Metrology, Korea Research Institute of Standards and Science (KRISS), Daejeon, 34133, Republic of Korea.
Ruthenium (Ru)-based electrocatalysts have shown promise for anion exchange membrane water electrolysis (AEMWE) due to their ability to facilitate water dissociation in the hydrogen evolution reaction (HER). However, their performance is limited by strong hydrogen binding, which hinders hydrogen desorption and water re-adsorption. This study reports the development of RuNi nanoalloys supported on MoO, which optimize the hydrogen binding strength at Ru sites through modulation by adjacent Ni atoms.
View Article and Find Full Text PDFPurification, characterization, and mechanistic studies of Gassericin GA-3.1: A novel class IIc bacteriocin produced by Lactobacillus gasseri LG145.
Int J Biol Macromol
January 2025
College of Engineering, China Agricultural University, Beijing 100083, China. Electronic address:
Bacteriocins, naturally derived antimicrobial peptides, are considered promising alternatives to traditional preservatives and antibiotics, particularly in food and medical applications. Despite extensive research on various bacteriocins, cyclic varieties remain understudied. This study introduces Gassericin GA-3.
View Article and Find Full Text PDFIon exchange chromatography of biotherapeutics: Fundamental principles and advanced approaches.
J Chromatogr A
January 2025
School of Pharmaceutical Sciences, University of Geneva, CMU - Rue Michel Servet 1, 1211 Geneva 4, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, CMU - Rue Michel Servet 1, 1211 Geneva 4, Switzerland. Electronic address:
Ion exchange chromatography (IEX) is an important analytical technique for the characterization of biotechnology-derived products, such as monoclonal antibodies (mAbs) and more recently, cell and gene therapy products such as messenger ribonucleic acid (mRNA) and adeno-associated viruses (AAVs). This review paper first outlines the basic principles and separation mechanisms of IEX for charge variant separation of biotherapeutics, and examines the different elution modes based on salt or pH gradients. It then highlights several recent trends when applying IEX for the characterization of biotechnology-derived products, including: i) the effective use of pH gradients, ii) the improvement of selectivity by using organic solvents in the mobile phase, multi-step gradients, or by combining ion pairing and ion exchange, and iii) the increase in analytical throughput using ultra-short columns or automated screening of conditions.
View Article and Find Full Text PDFStructural Dynamics of the Ubiquitin Specific Protease USP30 in Complex with a Cyanopyrrolidine-Containing Covalent Inhibitor.
J Proteome Res
January 2025
Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, U.K.
Inhibition of the mitochondrial deubiquitinating (DUB) enzyme USP30 is neuroprotective and presents therapeutic opportunities for the treatment of idiopathic Parkinson's disease and mitophagy-related disorders. We integrated structural and quantitative proteomics with biochemical assays to decipher the mode of action of covalent USP30 inhibition by a small-molecule containing a cyanopyrrolidine reactive group, . The inhibitor demonstrated high potency and selectivity for endogenous USP30 in neuroblastoma cells.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!