Membrane’s digest
MP
Structural basis for sugar perception by Drosophila gustatory receptors.
Demin Ma et al.,
Science 383, eadj2609 (2024).
doi:10.1126/science.adj2609
Insects rely on a family of gustatory receptors (GRs) to encode taste modalities.
Here: structures of Drosophila sweet taste receptors GR43a and GR64a in the apo and sugar-bound states.
GR43a is specifically activated by fructose that binds to a narrow pocket in ligand biding domain.
Sucrose and maltose selectively activate GR64a by binding to a larger and flatter pocket.
=> local conformational changes => channel opening.
Molecular insights into the determinants of substrate specificity and efflux inhibition of the RND efflux pumps AcrB and AdeB.
Wilhelm J, Pos KM.
Microbiology (Reading). 2024 Feb;170(2).
doi: 10.1099/mic.0.001438.
Overview of the molecular mechanisms of multiple drug efflux catalysed by the tripartite RND efflux system AcrAB-TolC from Eschericha coli. A comparison is made with the determinants for substrate binding of AdeB from Acinetobacter baumannii, which acts within the AdeABC multidrug efflux system.
HME, NFE, and HAE-1 efflux pumps in Gram-negative bacteria: a comprehensive phylogenetic and ecological approach.
Bodilis J, Simenel O, Michalet S, Brothier E, Meyer T, Favre-Bonté S, Nazaret S.
ISME Commun. 2024 Jan 10;4(1):ycad018.
doi: 10.1093/ismeco/ycad018.
Comprehensive phylogenetic and ecological study of RND permease: HME family, (metal resistance) = single clade (21.8% of all RND pumps), but the HAE-1 (hydrophobe/amphiphile efflux) and NFE (nodulation factor exporter) families have overlapping distributions.
This article proposes to restrict the HAE-1 family to 2 phylogenetic sister clades, representing 41.8% of all RND pumps and grouping most of the RND pumps involved in MDR.
There is a significant increase in genes encoding HME permeases in metal-contaminated environments.
Possibly related to their role in root colonization, genes encoding HAE-1 permeases are particularly abundant in the rhizosphere.
HAE-1 permeases are significantly less abundant in marine environments, whereas permeases of a new proposed HAE-4 family are predominant in the genomes of marine strains.
Using cryo-EM to understand the assembly pathway of respiratory complex I.
Laube E, Schiller J, Zickermann V, Vonck J.
Acta Crystallogr D Struct Biol. 2024 Mar 1.
doi: 10.1107/S205979832400086X.
Biogenesis of the complex I is a highly intricate process involving over 40 subunits encoded by nuclear or mitochondrial DNA and aided by at least 20 assembly factors.
Here: insights into the assembly process using cryo-EM.
Lipid-Dependent Activation of the Orphan G Protein-Coupled Receptor, GPR3.
Russell IC, Zhang X, Bumbak F, McNeill SM, Josephs TM, Leeming MG, Christopoulos G, Venugopal H, Flocco MM, Sexton PM, Wootten D, Belousoff MJ.
Biochemistry. 2024 Feb 20.
doi: 10.1021/acs.biochem.3c00647.
The orphan G protein-coupled receptor (GPCR) GPR3, associated with conditions like Alzheimer’s and premature ovarian failure, constitutively activates Gαs, leading to cAMP production, yet its endogenous ligand remains unknown.
Here: cryo-EM analysis of GPR3 in complex with DNGαs and Gβ1γ2 revealed a lipid-like ligand bound within a hydrophobic groove, potentially explaining its constitutive activity via ubiquitous lipid activation.
Mobile barrier mechanisms for Na+-coupled symport in an MFS sugar transporter.
Hariharan P, Shi Y, Katsube S, Willibal K, Burrows ND, Mitchell P, Bakhtiiari A, Stanfield S, Pardon E, Kaback HR, Liang R, Steyaert J, Viner R, Guan L.
Elife. 2024 Feb 21;12:RP92462.
doi: 10.7554/eLife.92462.
Despite numerous determined 3D structures of cation-coupled transporters, the precise mechanisms governing coupling and regulatory functions remain elusive. Here: a low-sugar affinity inward-facing Na+-bound cryoEM structure of the bacterial melibiose transporter (MelB) => substrate selectivity and intracellular release. Structural analysis, ITC, and MD => role of inner barrier dynamics in regulating substrate binding affinity without affecting cation binding, while HDX MS identified functionally important regions involved in barrier switching mechanisms for transport.
Consensus screening for a challenging target: the quest for P-glycoprotein inhibitors.
Governa P, Biagi M, Manetti F, Forli S.
RSC Med Chem. 2024 Jan 22;15(2):720-732.
doi: 10.1039/d3md00649b.
Using the human-mouse chimeric cryoEM 3D structure of the P-gp in the inhibitor-bound intermediate form (PDBID: 6qee), approximately 200 000 commercially available natural compounds from the ZINC database were virtually screened.
13 potential candidates were identified and then tested for their ability to inhibit P-gp, using zosuquidar, a third generation P-gp inhibitor, as a reference drug. Both retrospective and prospective results demonstrate the ability of the combined structure-based pharmacophore modeling and docking-based virtual screening approach to predict novel hit compounds with inhibitory activity toward P-gp.
Folding speeds of helical membrane proteins.
Min D.
Biochem Soc Trans. 2024 Feb 22:BST20231315.
doi: 10.1042/BST20231315.
Review exploring the folding speed aspect of multipass α-helical membrane proteins, encompassing plausible folding scenarios based on the timing and stability of helix packing interactions.
Membranes
Voltage tunes mGlu5 receptor function, impacting synaptic transmission.
Boutonnet M, Carpena C, Bouquier N, Chastagnier Y, Font-Ingles J, Moutin E, Tricoire L, Chemin J, Perroy J.
Br J Pharmacol. 2024 Feb 18.
doi: 10.1111/bph.16317.
Functional consequences of voltage sensitivity in GPCRs are not well understood.
Here: investigation of the voltage sensitivity of mGlu5 and its impact on synaptic transmission, using biosensors and electrophysiological recordings in non-excitable HEK293T cells or neurons.
mGlu5 receptor activity is directly regulated by membrane voltage which may have a significant impact on synaptic processes and pathophysiological functions.
Novel Screening System for Biliary Excretion of Drugs Using Human Cholangiocyte Organoid Monolayers with Directional Drug Transport.
Mizoi K, Okada R, Mashimo A, Masuda N, Itoh M, Ishida S, Yamazaki D, Ogihara T.
Biol Pharm Bull. 2024;47(2):427-433.
doi: 10.1248/bpb.b23-00655.
Cholangiocyte organoids derived from primary human hepatocytes = enhanced expression of bile duct epithelial markers and efflux transporters crucial for drug excretion. Membrane-cultured organoids exhibited distinct apical and basolateral membrane orientations with efflux transporters localized to the apical side, facilitating drug permeation studies. This novel cholangiocyte organoid monolayer system = promising for quantitatively assessing drug biliary excretion, offering a valuable screening model for evaluating the contribution of biliary excretion to drug clearance.
Amperometry and Electron Microscopy show Stress Granules Induce Homotypic Fusion of Catecholamine Vesicles.
Gu H, Gu C, Locker N, Ewing A.
Angew Chem Int Ed Engl. 2024 Feb 21:e202400422.
doi: 10.1002/anie.202400422.
Examination of the interaction between extracellular stress granules (SGs) and vesicles revealed that SG treatment led to larger vesicle formation and slower vesicle dynamics, suggesting homotypic fusion between large dense core vesicles (LDCVs). This fusion process, observed via amperometry and TEM, may represent a protective mechanism under high oxidative stress conditions in neurodegenerative diseases.
Lipid Microfluidic Biomimetic Models for Drug Screening: A Comprehensive Review
Eduarda Fernandes, Vanessa F. Cardoso, Senentxu Lanceros-Méndez, Marlene Lúcio.
Advanced Materials Technologies
doi.org/10.1002/adfm.202315166
Overview of both generations of lipid biomimetic models used in drug-membrane screening applications. Moreover, it delves into the intricacies of their production through microfluidic approaches and examines their screening applications in drug-membrane interaction. The review concludes with a critical analysis of potential future directions in this rapidly evolving field.
Molecules
Monitoring the response of a model protocell to dye and surfactant molecules through second harmonic generation and fluorescence imaging.
Li B, Li J, Chen S, Yuan Q, Fang C, Gan W.
Phys Chem Chem Phys. 2024 Feb 21.
doi: 10.1039/d4cp00009a.
Use of second-harmonic generation (SHG) and two-photon fluorescence (TPF) imaging to investigate the interaction of charged dye molecules with lipid vesicles
=> a unique approach that can provide detailed information on the interaction of molecules and lipids (both morphology and molecular kinetics).
Methods
Modeling membrane geometries implicitly in Rosetta.
Woods H, Leman JK, Meiler J.
Protein Sci. 2024 Mar;33(3):e4908.
doi: 10.1002/pro.4908.
Modifications to RosettaMP to enable modeling of MPs in various membrane geometries like micelles or nanodiscs. These modifications enhance core Rosetta applications such as structure refinement and protein-protein docking, leading to higher quality models more aligned with experimental structures, particularly when MPs are embedded in curved or multiple membranes, improving model discrimination and quality.
EncoMPASS: An encyclopedia of membrane proteins analyzed by structure and symmetry.
Aleksandrova AA, Sarti E, Forrest LR.
Structure. 2024 Feb 9:S0969-2126(24)00006-6.
doi: 10.1016/j.str.2024.01.011.
Description of the Encyclopedia of Membrane Proteins Analyzed by Structure and Symmetry (EncoMPASS) = a database for relating integral membrane proteins of known structure from the points of view of sequence, structure, and symmetry. EncoMPASS is accessible through a web interface, and its contents can be easily downloaded.
AlignScape, displaying sequence similarity using self-organizing maps.
Filella-Merce I, Mallet V, Durand E, Nilges M, Bouvier G, Pellarin R.
Front Bioinform. 2024 Jan 26;4:1321508.
doi: 10.3389/fbinf.2024.1321508.
AlignScape = new methodology based on self-organizing maps.
It provides a map of the similarity landscape and a tree representation of multiple sequence alignments.
Representations are useful to display, cluster, and classify sequences as well as identify functional trends.
Design of complicated all-α protein structures.
Sakuma K, Kobayashi N, Sugiki T, Nagashima T, Fujiwara T, Suzuki K, Kobayashi N, Murata T, Kosugi T, Tatsumi-Koga R, Koga N.
Nat Struct Mol Biol. 2024 Feb;31(2):275-282.
doi: 10.1038/s41594-023-01147-9.
Method to design complex α-helical protein structures by combining helix-loop-helix motifs and canonical α-helices, resulting in five distinct topologies
=> high thermal stability and fold into target structures.
=> Expands the scope of de novo protein design, offering opportunities to explore and engineer novel functional proteins within the vast landscape of protein structures.
Microbio
Identification of novel tail-anchored membrane proteins integrated by the bacterial twin-arginine translocase.
Gallego-Parrilla JJ, Severi E, Chandra G, Palmer T.
Microbiology (Reading). 2024 Feb;170(2).
doi: 10.1099/mic.0.001431.
Proteins are targeted to the Tat machinery by N-terminal signal peptides with a conserved twin-arginine motif, and some substrates are exported as heterodimers where the signal peptide is present on one of the partner proteins. A subset of Tat substrates is found in the membrane. Tat-dependent membrane proteins usually have large globular domains and a single transmembrane helix present at the N- or C-terminus. Five Tat substrates that have C-terminal transmembrane helices have previously been characterized in the model bacterium Escherichia coli.
Here: bioinformatic search to identify further tail-anchored Tat substrates encoded in bacterial genomes + experimental evidence (using reporter assays) that some have both N-terminal Tat signal peptides and C-terminal transmembrane helices. The newly identified proteins include a carboxypeptidase and a predicted protease, and four sortase substrates for which membrane integration is a prerequisite for covalent attachment to the cell wall.
Molecular basis and functional development of membrane-based microbial metabolism.
Yamada M.
Biosci Biotechnol Biochem. 2024 Feb 15:zbae018.
doi: 10.1093/bbb/zbae018.
Review on notable achievements in research on metabolisms: elucidation of the structure and function of membrane-bound glucose dehydrogenase, elucidation of expression regulation of several operons or by divergent promoters, elucidation of stress-induced programed-cell lysis and its requirement for survival during a long-term stationary phase, elucidation of molecular mechanism of survival at a critical high temperature, elucidation of thermal adaptation and its limit, isolation of thermotolerant fermenting yeast strains, and development of high-temperature fermentation and green energy production technologies.
Miscellaneous
THE story on Twitter last week: an AI-generated figure of a mouse with … prominent genitals. It appears that neither the editor nor the reviewers looked at the figures at all; the accompanying article (also AI-written) was peer reviewed in a couple of weeks.
Elisabeth Bik discusses this story in her blog:
How journals are fighting back against a wave of questionable images
Publishers are deploying AI-based tools to detect suspicious images, but generative AI threatens their efforts:
Nature 626, 697-698 (2024)
doi: https://doi-org.insb.bib.cnrs.fr/10.1038/d41586-024-00372-6
Generative AI’s environmental costs are soaring — and mostly secret
Nature 626, 693 (2024)
doi: https://doi-org.insb.bib.cnrs.fr/10.1038/d41586-024-00478-x
First-of-its-kind US bill would address the environmental costs of the technology, but there’s a long way to go.
Energetic laser pulses alter outcomes of X-ray studies of proteins
Nature 626, 720-722 (2024)
doi: https://doi-org.insb.bib.cnrs.fr/10.1038/d41586-024-00233-2
Modern X-ray sources have made it possible to follow the structural dynamics of proteins during biochemical processes, but the results have been questioned.
related article:
Barends, T.R.M., Gorel, A., Bhattacharyya, S. et al. Influence of pump laser fluence on ultrafast myoglobin structural dynamics. Nature 626, 905–911 (2024). https://doi-org.insb.bib.cnrs.fr/10.1038/s41586-024-07032-9
Brain drain from microbial research
doi: https://doi.org/10.1038/d41586-024-00534-6
A lack of funding from drug companies and governments is causing a ‘brain drain’ of scientists researching antimicrobial resistance (AMR), says the AMR Industry Alliance, an industry body. Since the 1990s, the workforce has halved, leading to a drop in research papers, and fewer drugs in development. At the same time, drug-resistant infections are undermining treatments that we have come to rely on and causing over a million deaths each year. An AMR report recommends new market incentives for antimicrobials, and training more early-career researchers to replenish the workforce before their knowledge and expertise disappear.
Super-speedy genome sequencing
Nature 626, 915-917 (2024)
doi: https://doi.org/10.1038/d41586-024-00483-0
Clinical geneticists are delivering rapid DNA sequencing that means their critically ill patients get timely and personalized treatment. Even a decade ago, whole-genome analysis was slow, expensive and unlikely to deliver actionable results. Now, some diagnoses arrive in less than a week, and the record is just over seven hours. When an ultra-rapid response is needed in oncology, clinicians can sometimes classify tumours in under an hour. Lowering costs for everyone and speeding up interpretation using artificial intelligence tools are the next steps.
Global eDNA project gears up for big day
doi: https://doi.org/10.1038/d41586-024-00520-y
In a first-of-its-kind global project, hundreds of community scientists in 101 countries will sample environmental DNA from the world’s lakes. Volunteers will receive instructions and a water-sampling filter to gather their samples on 22 May, the International Day for Biological Diversity. Researchers are hoping to detect the DNA of lake-dwelling animals and plants, as well as species that live upriver — possibly from the entire local region.
Introducing meat–rice: grain with added muscles beefs up protein
Nature 626, 703 (2024)
doi: https://doi-org.insb.bib.cnrs.fr/10.1038/d41586-024-00398-w
The laboratory-grown food uses rice as a scaffold for cultured meat.
Obesity drug cuts opiate craving
doi: 10.1126/science.z1i7yqc
A small clinical trial has shown that the blockbuster glucagon-like peptide-1 (GLP-1) drugs, already proven against obesity and type 2 diabetes, may reduce cravings in opiate addiction.
Vendor offering citations for purchase is latest bad actor in scholarly publishing
doi: 10.1126/science.zk7dou0
Unscrupulous researchers have many options for gaming citations metrics, new study highlights
What a tease! Great apes pull hair and poke each other for fun
Nature 626, 695 (2024)
doi: https://doi-org.insb.bib.cnrs.fr/10.1038/d41586-024-00410-3
The animals’ shenanigans hint that mischievous play evolved well before Homo sapiens did.