Membrane’s digest
MP
Structural basis for the modulation of MRP2 activity by phosphorylation and drugs.
Mazza T, Roumeliotis TI, Garitta E, Drew D, Rashid ST, Indiveri C, Choudhary JS, Linton KJ, Beis K.
Nat Commun. 2024 Mar 4;15(1):1983.
doi: 10.1038/s41467-024-46392-8. PMID: 38438394.
Cryo-EM structure of rat Mrp2 (rMrp2) in autoinhibited state and in complex with probenecid => unusual conformation where the regulatory domain is folded within the TM.
Phosphorylation of the regulatory domain relieves this autoinhibition, enhancing transport activity (confirmed by in vitro and human cell assays)
Drug-bound state suggests a dynamic interaction with autoinhibition, with mutations implicated in Dubin-Johnson syndrome interfering with conformational transitions.
Specific pharmacological and Gi/o protein responses of some native GPCRs in neurons.
Xu C, Zhou Y, Liu Y, Lin L, Liu P, Wang X, Xu Z, Pin JP, Rondard P, Liu J.
Nat Commun. 2024 Mar 5;15(1):1990.
doi: 10.1038/s41467-024-46177-z. PMID: 38443355.
Discovery of drugs targeting GPCRs and their G protein signaling properties are based on assays mainly performed with modified receptors expressed in heterologous cells but responses may differ in their native environment.
Here: highly sensitive Gi/o sensors => specific properties of Gi/o protein-mediated responses triggered by GABAB, α2 adrenergic and CB1 receptors in primary neurons, different from those in heterologous cells.
Reconstitution and resonance assignments of yeast OST subunit Ost4 and its critical mutant Ost4V23D in liposomes by solid-state NMR.
Chaudhary BP, Struppe J, Moktan H, Zoetewey D, Zhou DH, Mohanty S.
J Biomol NMR. 2024 Feb 29. doi: 10.1007/s10858-024-00437-8. Epub ahead of print. PMID: 38421550.
N-linked glycosylation => mannose-rich oligosaccharide transferred to a specific asparagine residue within a specific sequence motif by the enzyme oligosaccharyltransferase (OST).
Mutations in the yeast OST subunit Ost4 destabilize the enzyme and affect its function, as demonstrated by reconstitution experiments in lipid bilayers and ssNMR analysis (significant changes in chemical shifts upon mutation).
The open gate of the AMPA receptor forms a Ca2+ binding site critical in regulating ion transport.
Nakagawa T, Wang XT, Miguez-Cabello FJ, Bowie D.
Nat Struct Mol Biol. 2024 Feb 26.
doi: 10.1038/s41594-024-01228-3. PMID: 38409505.
AMPARs = critical ion channels facilitating fast excitatory neurotransmission in the brain.Mechanism of cation traversal through their pore has been elusive.
Here: investigation of the pore of Ca2+-permeable AMPARs => extracellular Ca2+ binding site becomes available when the channel gate opens, favoring Ca2+ movement into the pore.
A mutation associated with seizures, enhances channel opening but reduces Ca2+ binding, thereby diminishing Ca2+ permeability.
Silica Nanoparticles Decrease Glutamate Uptake in Blood-Brain Barrier Components.
Sánchez-Cano F, Hernández-Kelly LC, Ortega A.
Neurotox Res. 2024 Mar 4;42(2):20.
doi: 10.1007/s12640-024-00696-1. PMID: 38436780.
Silica nanoparticles (SiO2-NPs, commonly used in biomedical applications), may enter the circulatory system =>what is their impact on the blood-brain barrier (BBB) and glutamate transport systems ?
Here: while SiO2-NPs don’t affect cell viability, they decrease the uptake of radio-labeled D-aspartate (glutamate analog) in a dose-dependent manner, suggesting a disruption of BBB function and implicating potential adverse effects of air pollution on the central nervous system (CNS).
Cold temperature induces a TRPM8-independent calcium release from the endoplasmic reticulum in human platelets.
Stratiievska A, Filippova O, Özpolat T, Byrne D, Bailey SL, Chauhan A, Mollica MY, Harris J, Esancy K, Chen J, Dhaka AK, Sniadecki NJ, López JA, Stolla M.
PLoS One. 2024 Mar 4;19(3):e0289395.
doi: 10.1371/journal.pone.0289395. PMID: 38437228.
Platelets are sensitive to temperature changes (activated by decreased temperatures), similar to sensory neurons, though the underlying molecular mechanism remains unknown.
Here: demonstration of the presence of the temperature-sensitive ion channel TRPM8 in human platelets. Inhibition of TRPM8 prevents temperature-induced platelet activation. However, while TRPM8 appears involved in early temperature-induced platelet activation, later stages of temperature-mediated platelet response likely involve other mechanisms.
Role of Protonation States in the Stability of Molecular Dynamics Simulations of High-Resolution Membrane Protein Structures.
Lasham J, Djurabekova A, Zickermann V, Vonck J, Sharma V.
J Phys Chem B. 2024 Mar 2.
doi: 10.1021/acs.jpcb.3c07421. PMID: 38430110.
A limitation of conventional MD is that the protonation states of titratable amino acid residues remain fixed during simulations.
Here: classical MD simulations on high-resolution cryo-EM structures of two large MPs that transfer protons by catalyzing protonation/deprotonation reactions (respiratory complex I from Yarrowia lipolytica and multiple resistance and pH adaptation (Mrp) cation/proton antiporter from Bacillus pseudofirmus).
take home message: it is crucial to perform basic protonation state calculations prior to the launch of any conventional MD simulations.
Membrane
Phosphoinositide switches in cell physiology – from molecular mechanisms to disease.
Lolicato F, Nickel W, Haucke V, Ebner M.
J Biol Chem. 2024 Feb 14:105757.
doi: 10.1016/j.jbc.2024.105757. PMID: 38364889.
Rather than serving as mere structural elements of lipid bilayers, phosphoinositides represent molecular switches for a broad range of biological processes, including cell signaling, membrane dynamics and remodeling, and many other functions.
Here: focus on the molecular mechanisms that turn phosphoinositides into molecular switches and how the dysregulation of these processes can lead to disease.
Membrane lipids drive formation of KRAS4b-RAF1 RBDCRD nanoclusters on the membrane.
Shrestha R, Carpenter TS, Van QN, Agamasu C, Tonelli M, Aydin F, Chen D, Gulten G, Glosli JN, López CA, Oppelstrup T, Neale C, Gnanakaran S, Gillette WK, Ingólfsson HI, Lightstone FC, Stephen AG, Streitz FH, Nissley DV, Turbyville TJ.
Commun Biol. 2024 Feb 28;7(1):242.
doi: 10.1038/s42003-024-05916-0. PMID: 38418613.
Details of protein-protein and protein-lipid interactions in RAS-mediated signaling remain elusive.
Here: experimental techniques and computational modeling to investigate KRAS4b and RAF1 on lipid bilayers, revealing that RBDCRD (KRAS-RAF1 complex) binding alters KRAS diffusion, promotes cluster formation, and stabilizes complexes through membrane penetration, suggesting cooperative interactions critical for MAP kinase signal activation.
Capturing of extracellular vesicles derived from single cells of Escherichia coli.
Yokoyama F, Kling A, Dittrich PS.
Lab Chip. 2024 Mar 1. doi: 10.1039/d3lc00707c. PMID: 38426311.
Investigates of the secretion of extracellular vesicles (EVs) by bacteria, in the context of antibiotic resistance.
A microfluidic device is introduced to culture single bacterial cells and capture EVs they secrete => variations in EV secretion among individual bacteria, especially under antibiotic treatment.
+ the method selectively captures and detects EVs in the microfluidic device.
The device traps single rod-shaped E. coli cells, allowing observation of changes in cell length and growth dynamics in response to antibiotics, with on-chip-cultured cells showing higher susceptibility compared to bulk culture.
The intricate link between membrane lipid structure and composition and membrane structural properties in bacterial membranes.
Lee TH, Charchar P, Separovic F, Reid GE, Yarovsky I, Aguilar MI.
Chem Sci. 2024 Jan 31;15(10):3408-3427.
doi: 10.1039/d3sc04523d. PMID: 38455013.
Biomembrane = fluid self-assembled nanostructure but the link between the lipid components and the structural properties of the lipid bilayer are not well understood.
Here: perspective on the factors that regulate bilayer structure and flexibility: selection of recent studies that address the dynamic nature of bacterial lipid diversity and membrane properties in response to stress conditions.
Sensing membrane voltage by reorientation of dipolar transmembrane peptides.
Bisht K, Lomholt MA, Khandelia H.
Biophys J. 2024 Mar 5;123(5):584-597.
doi: 10.1016/j.bpj.2024.01.037. PMID: 38308436.
Membrane voltage = vital role in the behavior and functions of the lipid bilayer membrane.
Here: study the membrane voltage-sensing mechanism, which entails the reorientation of α-helices with a change in the membrane voltage.
Extensive MD to study the effect of variation of membrane voltage on the tilt angle of peptides => optimal parameters for designing such a voltage-sensing peptide.
+ investigation of the interplay of competing effects of hydrophobic mismatch and dipole-electric field coupling on the tilt of the peptide.
Molecules
Strain-Promoted Cycloadditions in Lipid Bilayers Triggered by Liposome Fusion.
Jumeaux C, Spicer CD, Charchar P, Howes PD, Holme MN, Ma L, Rose NC, Nabarro J, Fascione MA, Rashid MH, Yarovsky I, Stevens MM.
Angew Chem Int Ed Engl. 2024 Mar 4:e202314786.
doi: 10.1002/anie.202314786. PMID: 38438780.
SPAAC = ”specifically strain promoted azide-alkyne cycloaddition” => novel approach using bioorthogonal reactions within lipid bilayers.
By utilizing azide- and strained alkyne-functionalized FRET dye pairs, the SPAAC reaction between diffusing molecules inside liposomal membranes is characterized for the first time.
=> potential applications: in situ bioorthogonal labeling of MPs, enhanced understanding of membrane dynamics, and the development of new probes for biosensing assays.
Exploring the Physical Properties of Lipid Membranes with Polyhydroxy Oxanorbornane Head Group Using NBD-Conjugated and DPH Fluorescent Probes.
Sahu AK, Reddy UC, Kannoth Manheri M, Mishra AK.
Langmuir. 2024 Mar 1.
doi: 10.1021/acs.langmuir.3c02941. PMID: 38427698.
Investigation of the physical properties of lipid membranes with polyhydroxy oxanorbornane (PH-ONB) headgroups, mimicking archaeal lipid membranes => stable bilayers.
Using fluo, authors study the characteristics of NBD-tagged ONB-based lipids => polarity, fluidity, and phase transition using NBD-tagged probes and DPH.
=> ONB-based membranes exhibit characteristics akin to phospholipid membranes, with higher phase transition temperatures.
Methods
Generalized biomolecular modeling and design with RoseTTAFold All-Atom.
Rohith Krishna et al.,
Science 0, eadl2528
RoseTTAFold All-Atom (RFAA) = combines a residue-based representation of amino acids and DNA bases with an atomic representation of all other groups to model assemblies containing proteins, nucleic acids, small molecules, metals, and covalent modifications given their sequences and chemical structures. By fine tuning on denoising tasks we obtain RFdiffusionAA, which builds protein structures around small molecules.
Starting from random distributions of amino acid residues surrounding target small molecules, the authors design and experimentally validate, through crystallography and binding measurements, proteins that bind the cardiac disease therapeutic digoxigenin, the enzymatic cofactor heme, and the light harvesting molecule bilin.
😳😱🤯
Pro-SMP finder-A systematic approach for discovering small membrane proteins in prokaryotes.
Hoffman T, Kinne J, Cho KH.
PLoS One. 2024 Feb 29;19(2):e0299169.
doi: 10.1371/journal.pone.0299169. PMID: 38422081.
Prokaryotic ORFs < 200 bases = often overlooked by HT-proteomics methods.
Many of these small proteins are membrane proteins with a single membrane-anchoring α-helix, identifiable using computational algorithms like Phobius and TMHMM.
Here: systematic approach with algorithms such as Orfipy and Blast => identification of small MPs in prokaryotic organisms, revealing their prevalence and distribution across genomes, including intergenic regions.
Software pipeline and online interface: http://cs.indstate.edu/pro-smp-finder.
Steric trapping strategy for studying the folding of helical membrane proteins.
Yao J, Hong H.
Methods. 2024 Feb 28:S1046-2023(24)00059-8.
doi: 10.1016/j.ymeth.2024.02.007. PMID: 38428472.
Review discussing the methodological advancements, limitations, and future prospects of steric trapping as a method to understand the folding energy landscape of MPs. Steric trapping offers reversible control of MP folding with minimal disruption to native interactions (spontaneous denaturation of doubly biotinylated proteins coupled with binding of bulky streptavidin molecules).
Real-Time Biosynthetic Reaction Monitoring Informs the Mechanism of Action of Antibiotics.
Oluwole AO, Hernández-Rocamora VM, Cao Y, Li X, Vollmer W, Robinson CV, Bolla JR.
J Am Chem Soc. 2024 Mar 1.
doi: 10.1021/jacs.4c00081. PMID: 38428018.
Native mass spectrometry for monitoring biosynthetic reactions of membrane enzymes in real-time.
Here: real-time monitoring of bacterial membrane phosphatases UppP and PgpB activities, demonstrating their inhibition by antibiotics like bacitracin and teixobactin. Unexpectedly, PE was found to stabilize the UppP dimer and enhance substrate processing speed.
Mutational analysis in Corynebacterium stationis MFS transporters for improving nucleotide bioproduction.
Kinose K, Shinoda K, Konishi T, Kawasaki H.
Appl Microbiol Biotechnol. 2024 Mar 4;108(1):251.
doi: 10.1007/s00253-024-13080-y. PMID: 38436751.
This study investigates nucleotide secretion by engineered Corynebacterium stationis, revealing a hyperactive mutation in a nucleotide-exporting MFS transporter.
Structural analysis and MD suggest that the mutation enhances transporter activity by strengthening interactions between TM helices and facilitating substrate release from the cavity.
Direct single-molecule detection of CoA-SH and ATP by the membrane proteins TMEM120A and TMEM120B.
Zhao C, Chen M, Liu X, Yuan W, Li K, Wang Y, Chen C, Zhang M, Dong Y, Xiao Y, Deng D, Geng J.
Nanoscale. 2024 Mar 6.
doi: 10.1039/d3nr05054h. PMID: 38444242.
Ion transport properties of TMEM120A and TMEM120B on an artificial lipid bilayer using single-channel recording.
Stable ion transport capabilities + TMEM120A’s binding with coenzyme A (CoA-SH) => the proteins were developed into single-molecule sensors for detecting COA-SH and structurally similar molecules.
Both CoA-SH and ATP were shown to reversibly bind to single TMEM120A and TMEM120B proteins embedded in the lipid bilayer (blocking of ion currents).
Cell-free translation system with artificial lipid-monolayer particles as a unique tool for characterizing lipid-monolayer binding proteins.
Kuroiwa F, Suda H, Yabuki M, Atsuzawa K, Yamaguchi H, Toyota M, Kaneko Y, Yamashita S, Takahashi S, Tozawa Y.
Biosci Biotechnol Biochem. 2024 Mar 5:zbae026.
doi: 10.1093/bbb/zbae026. PMID: 38444196.
Functional analysis of proteins localized to lipid monolayers like rubber particles and lipid droplets faces methodological limitations.
Here: system where artificially prepared lipid monolayer particles are incorporated into a cell-free translation system, allowing confirmation of protein properties binding specifically to lipid monolayers in a translation-coupled manner.
Rapid simulation of glycoprotein structures by grafting and steric exclusion of glycan conformer libraries.
Tsai YX, Chang NE, Reuter K, Chang HT, Yang TJ, von Bülow S, Sehrawat V, Zerrouki N, Tuffery M, Gecht M, Grothaus IL, Colombi Ciacchi L, Wang YS, Hsu MF, Khoo KH, Hummer G, Hsu SD, Hanus C, Sikora M.
Cell. 2024 Feb 29;187(5):1296-1311.e26.
doi: 10.1016/j.cell.2024.01.034. PMID: 38428397.
Highly mobile nature of glycans complicates structural elucidation. GlycoSHIELD = method that efficiently grafts realistic ensembles of glycan conformers onto static protein structures.
DNA-functionalized artificial mechanoreceptor for de novo force-responsive signaling.
Yang S, Wang M, Tian D, Zhang X, Cui K, Lü S, Wang HH, Long M, Nie Z.
Nat Chem Biol. 2024 Mar 6.
doi: 10.1038/s41589-024-01572-x. PMID: 38448735.
Artificial mechanoreceptors capable of rewiring non-mechanoresponsive receptor tyrosine kinases (RTKs) to sense user-defined force cues, facilitating de novo-designed mechanotransduction.
AMR = modular DNA-protein chimera = mechanosensing DNA nanodevice onto natural RTKs via aptameric anchors.
Allosteric DNA mechano-switch => AMR senses intercellular tensile force, enabling force-triggered dynamic DNA assembly to manipulate RTK dimerization and activation of intracellular signaling.
By swapping force-reception ligands, AMR mediates c-Met and FGFR1 activation in response to cellular tensile forces mediated by adhesion proteins or membrane protein endocytosis
=> customizable mechanobiological functions such as neural stem cell maintenance !
MagIC-Cryo-EM: Structural determination on magnetic beads for scarce macromolecules in heterogeneous samples
Yasuhiro Arimura, Hide A. Konishi, Hironori Funabiki
bioRxiv 2024.01.21.576499;
doi: https://doi.org/10.1101/2024.01.21.576499
Magnetic Isolation and Concentration (MagIC)-cryo-EM => high-resolution structural analysis of biomolecules captured on magnetic beads, significantly reducing the concentration requirement to < 0.0005 mg/ml.
Additionally, employing Duplicated Selection To Exclude Rubbish particles (DuSTER), low signal-to-noise ratio particles were removed
Miscellaneous
Why we like dessert
Cell Metab. (2024) 10.1016/j.cmet.2023.12.014
Signals from ingested sugars and fats separately activate neurons communicating between the gut and brain.
=> connect to dopamine-mediated reward circuits
=> enhancing the reward signal (and potentially promoting overeating).
‘Epigenetic’ editing cuts cholesterol in mice
Nature 627, 14-15 (2024)
doi: https://doi-org.insb.bib.cnrs.fr/10.1038/d41586-024-00563-1
Changes to chemical tags on DNA in mice dial down the activity of a gene without cuts to the genome.
Is ChatGPT making scientists hyper-productive? The highs and lows of using AI
Nature 627, 16-17 (2024)
doi: https://doi-org.insb.bib.cnrs.fr/10.1038/d41586-024-00592-w
Large language models are transforming scientific writing and publishing. But the productivity boost that these tools bring could have a downside.
Neuralink brain chip: advance sparks safety and secrecy concerns
Nature 627, 19 (2024)
doi: https://doi-org.insb.bib.cnrs.fr/10.1038/d41586-024-00550-6
Elon Musk announced this week that his company’s brain implant has allowed a person to move a computer mouse with their mind.
An innovative way for whales to sing
Nature 627, 40-42 (2024)
doi: https://doi-org.insb.bib.cnrs.fr/10.1038/d41586-024-00307-1
Mammals make sounds when air flow causes paired tissue folds in their voice box to oscillate. However, such air flow in the baleen group of whales takes an unusual path, enabling them to make sounds in a previously unknown way.
Where we also learn that whales generate star wars, lightsaber sounds.
May the force be with them !
Gedamke J, Costa DP, Dunstan A. Localization and visual verification of a complex minke whale vocalization.
J Acoust Soc Am. 2001 Jun;109(6):3038-47.
doi: 10.1121/1.1371763. PMID: 11425146.
Artificial intelligence and illusions of understanding in scientific research.
Messeri L, Crockett MJ.
Nature. 2024 Mar;627(8002):49-58.
doi: 10.1038/s41586-024-07146-0. Epub 2024 Mar 6. PMID: 38448693.
Implementation of AI => risks:
* exploitation of cognitive biases => illusions of understanding and hindering scientific innovation).
* favoring certain methods, questions, and viewpoints while neglecting alternative approaches.
A mobile DNA sequence could explain tail loss in humans and apes
Nature 626, 958-959 (2024)
doi: https://doi-org.insb.bib.cnrs.fr/10.1038/d41586-024-00309-z
The lack of a tail is one thing that separates apes — including humans — from other primates. Insertion of a short DNA sequence into a gene that controls tail development could explain tail loss in the common ancestor of apes.