Membrane’s digest
MP
The structure and function of olfactory receptors.
Wu C, Xu M, Dong J, Cui W, Yuan S.
Trends Pharmacol Sci. 2024 Jan 30:S0165-6147(24)00004-X.
doi: 10.1016/j.tips.2024.01.004.
Olfactory receptors (ORs) belong to the class A GPCRs.
Recent research => ORs are involved in many nonolfactory physiological processes in extranasal tissue: brain, pancreas, and testes … possible role of their dysregulation in various diseases.
In this review: recent developments and computational modeling efforts.
Discovery and structural characterization of the D-box, a conserved TonB motif that couples an inner-membrane motor to outer-membrane transport.
Loll PJ, Grasty KC, Shultis DD, Guzman NJ, Wiener MC.
J Biol Chem. 2024 Feb 2:105723.
doi: 10.1016/j.jbc.2024.105723.
Gram-negative bacteria use TonB-dependent transport to take up nutrients from the external environment. Much is known about the interaction between TonB and OM transporters but the critical interface between TonB and ExbBD is less well understood.
Here: identification of a conserved motif within TonB (termed ”D-box”) = attachment point for ExbD. Characterization of the interaction both functionally and structurally.
Escherichia coli resistance mechanism AcrAB-TolC efflux pump interactions with commonly used antibiotics: a molecular dynamics study.
Smith BL, Fernando S, King MD.
Sci Rep. 2024 Feb 1;14(1):2742.
doi: 10.1038/s41598-024-52536-z.
MD to visualize some of the changes occurring within AcrAB-TolC at a molecular level when airborne bacteria are exposed to stress and antibiotics (previous experimental research showed an increase in antibiotic resistance and efflux pump activity when exposed to aerosolization).
comparison of the effect of aerosolization on the binding to puromycin (PUY), ampicillin (AMP) and sulfamethoxazole-trimethoprim (SXT) to the AcrB binding site.
=> more flexibility in the proteins within simulations conducted under standard pressure for the AcrB protein and the full tripartite complex: increased pressure causes more rigidity.
Free energy of ligand-protein binding did not show a significant change, but the strongest scores were for ligands that moved to another binding pocket and did not result in resistance or opening of the efflux pump.
AMP under increased pressure showed the largest change in opening of TolC and aligns with experimental data showing E. coli cells had the most resistance to AMP after aerosolization.
TRAPs: the ‘elevator-with-an-operator’ mechanism.
Davies JS, Currie MJ, Dobson RCJ, Horne CR, North RA.
Trends Biochem Sci. 2024 Feb;49(2):134-144.
doi: 10.1016/j.tibs.2023.11.006. Epub
TRAP transporters (Tripartite ATP-independent periplasmic transporters) = nutrient-uptake systems found in bacteria and archaea.
They couple a substrate-binding protein (SBP) to an elevator-type secondary transporter= first-of-its-kind mechanism of transport.
Here: highlight of TRAP transporter structures and recent functional data + discussion on recent structural and biophysical studies of the ion transporter superfamily => mechanistic principles for TRAP transporter system.
Transport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain.
Mao YX, Chen ZP, Wang L, Wang J, Zhou CZ, Hou WT, Chen Y.
Nat Commun. 2024 Feb 5;15(1):1061.
doi: 10.1038/s41467-024-45337-5.
Bilirubin = mainly generated from the breakdown of heme when red blood cells reach the end of their lifespan. Bilirubin accumulation in human body => various disorders (including jaundice and liver disease). Bilirubin is conjugated in hepatocytes and excreted to bile duct via ABCC2.
Here: structures of ABCC2 in the apo, substrate-bound and ATP/ADP-bound forms using the cryo-EM => full transporter with a regulatory (R) domain inserted between the two half modules.
+ Substrate-stimulated ATPase and transport activity assays => upon substrate binding, the R domain is expelled from the cavity and docks to the lateral of transmembrane domain following ATP hydrolysis.
Transport and inhibition mechanisms of human VMAT2.
Wu, D., Chen, Q., Yu, Z. et al.
Nature 626, 427–434 (2024).
https://doi-org.insb.bib.cnrs.fr/10.1038/s41586-023-06926-4
Structures of human vesicular monoamine transporter 2 in complexes with serotonin and three clinical drugs provide insights into the structural basis for serotonin transport and inhibition of transporter activity by the drugs.
Membranes
Charge of a transmembrane peptide alters its interaction with lipid membranes.
Thakur GCN, Uday A, Cebecauer M, Roos WH, Cwiklik L, Hof M, Jurkiewicz P, Melcrová A.
Colloids Surf B Biointerfaces. 2024 Jan 23;235:113765.
doi: 10.1016/j.colsurfb.2024.113765.
TM proteins interact closely with the surrounding membrane lipids. Lipids in the vicinity of TM proteins were reported to have hindered mobility, which has been associated with lipids being caught up in the rough surface of the TM domains.
Electrostatics of the TM peptide is oftent neglected (they are usually positively charged at their cytosolic end).
Here: study how the charge of a TM peptide influences the membrane (time dependent fluorescent shift in combination with FRET, AFM, MD).
Introduction of a positive charge to the peptide enhances lateral heterogeneity in lipid mobility, free lipid rearrangement and lowers the membrane ability to seal ruptures after mechanical indentations.
Use of bacterial photosynthetic vesicles to evaluate the effect of ionic liquids on the permeability of biological membranes.
Bin T, Venturoli G, Ghelli AM, Francia F.
Biochim Biophys Acta Biomembr. 2024 Jan 29:184291.
doi: 10.1016/j.bbamem.2024.184291.
Ionic liquids (ILs) = salts composed of a combination of organic or inorganic cations and anions characterized by a low melting point (< 100 °C).
Here: study of the interaction of ILs with native biological membranes by using photosynthetic vesicles from Rhodobacter capsulatus.
Carotenoids associated with the LHCII, act as endogenous spectral probes of the transmembrane electrical potential (ΔΨ).
=> some ILs cause a rather fast dissipation of the ΔΨ even at low concentrations, in dose-dependent manner.
Molecules
Solubilization of Oligomeric Cell-Free Synthesized Proteins Using SMA Copolymers.
Ullrich J, Haueis L, Ohlhoff C, Zemella A, Kubick S, Stech M.
Methods Mol Biol. 2024;2762:293-308.
doi: 10.1007/978-1-0716-3666-4_18.
Chapter presenting synthesis platform based on eukaryotic cell-free protein synthesis (CFPS) and an efficient solubilization strategy using SMA copolymers.
Advances in membrane mimetic systems for manipulation and analysis of membrane proteins; detergents, polymers, lipids and scaffolds.
Woubshete M, Cioccolo S, Byrne B.
Chempluschem. 2024 Feb 5:e202300678.
doi: 10.1002/cplu.202300678.
Last 15 years or so = veritable explosion in the development of novel detergents with improved properties.
Review of the recent advances with respect to these new agents and systems for membrane protein extraction, reconstitution and analysis.
Methods
Expanding Native Mass Spectrometry to the Masses.
Harvey SR, Gadkari VV, Ruotolo BT, Russell DH, Wysocki VH, Zhou M.
J Am Soc Mass Spectrom. 2024 Feb 1.
doi: 10.1021/jasms.3c00352.
Commentary summarizing the discussion and current initiatives to address challenges facing the field of native mass spectrometry and approaches to expanding the field to nonexperts, during the 33rd ASMS Sanibel Meeting, on Membrane Proteins and Their Complexes.
A time-resolved Förster resonance energy transfer assay to investigate drug and inhibitor binding to ABCG2.
Mitchell-White JI, Briggs DA, Mistry SJ, Mbiwan HA, Kellam B, Holliday ND, Briddon SJ, Kerr ID.
Arch Biochem Biophys. 2024 Jan 31:109915.
doi: 10.1016/j.abb.2024.109915.
Detailed knowledge of ABCG2 activity is crucial for understanding drug transport and resistance in cancer, and has implications for wider pharmacokinetics.
Here: novel binding assay using a high affinity fluorescent inhibitor and time-resolved FRET to measure saturation binding to ABCG2. Adaptable for other multidrug pumps.
De novo design of high-affinity binders of bioactive helical peptides.
Vázquez Torres, S., Leung, P.J.Y., Venkatesh, P. et al.
Nature 626, 435–442 (2024).
https://doi-org.insb.bib.cnrs.fr/10.1038/s41586-023-06953-1
Many peptide hormones form an α-helix on binding their receptors. De novo protein design can now generate binders with high affinity and specificity to structured proteins.
Here: description of the parametric generation and deep learning-based methods for designing proteins to address the challenge of designing interactions between proteins and short peptides with helical propensity.
Microbio
The journey to understand previously unknown microbial genes
Nature 626, 267-269 (2024)
doi: https://doi-org.insb.bib.cnrs.fr/10.1038/d41586-024-00077-w
The analysis of DNA sequences sheds light on microbial biology, but it is difficult to assess the function of genes that have little or no similarity to characterized genes. In this paper, scientists discuss this challenge from genomic and microbial perspectives.
In Silico Screening and Experimental Validation of Novel MexAB-OprM Efflux Pump Inhibitors of Pseudomonas aeruginosa.
Abdelmalek S, Hajar M, Salah L, Abdel-Halim H.
Microb Drug Resist. 2024 Feb;30(2):73-81.
doi: 10.1089/mdr.2023.0126.
Structure-based virtual screening techniques for the identification of new MexAB-OprM efflux inhibitors. The predicted poses filtered by induced fit docking procedures + in vitro microbiological assays for the validation of in silico results. Two compounds were able to restore tetracycline susceptibility in MexAB-OprM overexpressing Pseudomonas aeruginosa ATCC® 27853™ strain.
Required criteria of drug efflux pump inhibitors to disrupt the function of AcrB subunit protein from AcrAB-TolC multidrug efflux pump from Escherichia coli
Rawaf Alenazy
https://www.sciencedirect.com/science/article/pii/S1018364724000284
The drug efflux pumps inhibition approach is emerging as a new attractive and promising approach in reversing antibiotic resistance in many clinically relevant pathogenic bacteria. This review discusses the requirements that must be met in inhibitors that target AcrB.
Daptomycin avoids drug resistance mediated by the BceAB transporter in Streptococcus pneumoniae.
Faure A, Manuse S, Gonin M, Grangeasse C, Jault J-M, Orelle C.
Microbiol Spectr. 2024 Feb 6;12(2):e0363823.
doi: 10.1128/spectrum.03638-23.
The lipopeptide daptomycin is an antibiotic that selectively disrupts Gram-positive bacterial membranes
=> slower resistance development than many classical drugs.
=> often used as a last resort antibiotic.
Mode of action of daptomycin = formation of a tripartite complex between undecaprenyl precursors of cell wall biosynthesis and the anionic phospholipid PG.
Here: investigation whether daptomycin evades resistance mediated by the BceAB transporter from Streptococcus pneumoniae. Although daptomycin can bind to the transporter, data showed that the BceAB transporter does not mediate resistance to the drug and its expression is not induced in its presence
=> daptomycin has the potential to escape the resistance mechanism mediated by BceAB-type transporters.
PQS and pyochelin in Pseudomonas aeruginosa share inner membrane transporters to mediate iron uptake.
Zhang H, Yang J, Cheng J, Zeng J, Ma X, Lin J.
Microbiol Spectr. 2024 Feb 6;12(2):e0325623.
doi: 10.1128/spectrum.03256-23.
PQS and pyochelin in P. aeruginosa share inner membrane transporters such as FptX, PchHI, and FepBCDG to mediate iron uptake. Meanwhile, PQS and pyochelin-mediated signaling operate to a large extent via these inner membrane transporters. The study reveals the existence of shared uptake pathways between PQS and pyochelin, which could lead us to reexamine the role of these two molecules in the iron uptake and virulence of P. aeruginosa.
Miscellaneous
Extracellular membrane vesicles derived from Komagataeibacter oboediens exposed on the International Space Station fuse with artificial eukaryotic membranes in contrast to vesicles of reference bacterium.
Orlovska I, Zubova G, Shatursky O, Kukharenko O, Podolich O, Gorid’ko T, Kosyakova H, Borisova T, Kozyrovska N.
Biochim Biophys Acta Biomembr. 2024 Jan 26;1866(3):184290.
doi: 10.1016/j.bbamem.2024.184290.
EVs of nonpathogenic bacteria deliver their contents by endocytosis into eukaryotic cells, however, no evidence exists for a fusion delivery mechanism.
Here: description of the fusion of exposed to space/Mars-like stressors simulated on the International Space Station vesicles (E-EVs) from Komagataeibacter oboediens to different types of model planar membranes in comparison with the EVs of the ground-based reference strain.
Elon Musk’s Neuralink brain chip: what scientists think of first human trial
doi: https://doi.org/10.1038/d41586-024-00304-4
Brain-computer-interface company Neuralink has reportedly implanted its ‘brain-reading’ device into a person for the first time. The implant is designed to record and decode individual neurons’ activity, with the aim of allowing a person with severe paralysis to control, for example, a robotic arm. Experts are cautiously excited: this is the first fully wireless device of its kind, and it has more brain connections than other systems. There is frustration about Neuralink’s lack of transparency: there’s little information about the study and a tweet by the company’s founder, controversial entrepreneur Elon Musk, is the only confirmation that the trial has begun.
Obesity drugs have another superpower: taming inflammation
Nature 626, 246 (2024)
doi: https://doi-org.insb.bib.cnrs.fr/10.1038/d41586-024-00118-4
The blockbuster medications that reduce body weight also reduce inflammation in organs such as the brain, raising hopes that they can treat Parkinson’s and Alzheimer’s diseases.
Hidden effects of science competitions
Melissa McCartney
J. Res. Sci. Teach. (2023) 10.1002/tea.21901
Science competitions are meant to encourage student interest in science and science careers, and evaluations typically focus on positive outcomes and successful competitors. Here: examination of the effects of early elimination.
=> for participants placing high importance on advancing in the competition, elimination interfered with the development of study and career expectations.
We finally know why flying insects flock to artificial lights at night
Contrary to long-held beliefs, these arthropods are not attracted to our lights, but are actually disoriented and panicked by them.