MP
Architecture and activation of single-pass transmembrane receptor guanylyl cyclase.
Liu S, Payne AM, Wang J, Zhu L, Paknejad N, Eng ET, Liu W, Miao Y, Hite RK, Huang XY.
Nat Struct Mol Biol. 2024 Nov 14.
doi: 10.1038/s41594-024-01426-z. Epub ahead of print.
PMID: 39543315.
The heart produces natriuretic peptides, which regulate blood pressure through the guanylyl cyclase A (GC-A) receptor => cyclic GMP generation.
Here: cryoEM and MD => structure of full-length human GC-A, shedding light on its architecture and the interactions that occur during receptor activation.
Endomembrane GPCR signaling: 15 years on, the quest continues.
Calebiro D, Miljus T, O’Brien S.
Trends Biochem Sci. 2024 Nov 11:S0968-0004(24)00231-7.
doi: 10.1016/j.tibs.2024.10.006. Epub ahead of print.
PMID: 39532582.
GPCRs play a key role in human physiology, disease, and pharmacology but recent research has revealed that they also signal on the membranes of intracellular organelles, such as endosomes and the Golgi complex, in addition to the plasma membrane.
Here: review highlighting recent advancements in understanding endomembrane GPCR signaling and its potential therapeutic applications.
Conditionally Activatable Chimeras for Tumor-Specific Membrane Protein Degradation.
Liu H, Fu Z, Han Y, Fang Y, Shen W, Chen Z, Zhu R, Zhang H, Chen PR.
J Am Chem Soc. 2024 Nov 19.
doi: 10.1021/jacs.4c06160. Epub ahead of print.
PMID: 39561381.
Recent advancements in membrane protein degraders (MPDs) have expanded the use of proteolysis-targeting chimeras (PROTACs) to target previously “undruggable” cell-surface proteins.
Here: introduction of a conditionally activatable membrane protein degrader (Pro-MPD) to decrease off-target degradation and toxicity.
=> Biparatopic nanobodies + tumor-specific cell-penetrating peptide => effectively degradation PD-L1 in tumor sites, reactivates T cells, and inhibits tumor growth, offering a safer, more efficient approach for in vivo applications.
A literature review of drug transport mechanisms during lactation.
Gong C, Bertagnolli LN, Boulton DW, Coppola P.
CPT Pharmacometrics Syst Pharmacol. 2024 Nov;13(11):1870-1880.
doi: 10.1002/psp4.13195. Epub 2024 Jul 7.
PMID: 38973229.
Literature review on the mechanisms of drug transport to breastmilk, including passive transport, active transport, lipid co-transport, and transcytosis.
The structures of protein kinase A in complex with CFTR: Mechanisms of phosphorylation and noncatalytic activation.
Fiedorczuk K, Iordanov I, Mihályi C, Szollosi A, Csanády L, Chen J.
Proc Natl Acad Sci U S A. 2024 Nov 12;121(46):e2409049121.
doi: 10.1073/pnas.2409049121. Epub 2024 Nov 4.
PMID: 39495916.
Protein kinase A regulates cellular functions by phosphorylating various substrates, including ion channels like CFTR.
Here: cryoEM structures of PKA’s catalytic subunit bound to CFTR.
Reveals how unphosphorylated CFTR interacts with PKA-C at two catalytic stations, => flexible phosphorylation of multiple sites.
+ structures of open-pore CFTR stabilized by PKA-C, => insights into how PKA-C stimulates CFTR currents even without phosphorylation.
Structure of an ex vivoDrosophila TOM complex determined by single-particle cryoEM.
Periasamy A, Ornelas P, Bausewein T, Mitchell N, Zhao J, Quinn LM, Kuehlbrandt W, Gulbis JM.
IUCrJ. 2025 Jan 1.
doi: 10.1107/S2052252524011011. Epub ahead of print.
PMID: 39575538.
TOM in mitochondria = primary protein-import pore, recognizing and transferring mitochondrial precursor proteins from the cytoplasm across the outer membrane.
Here: 3.3 Å resolution map and molecular model of the TOM complex from Drosophila melanogaster (guess what … by SPA cryoEM !)
=> first structural analysis of a transgenic protein expressed and purified ex vivo from Drosophila.
Functionally important binding site for a volatile anesthetic in a voltage-gated sodium channel identified by X-ray crystallography.
Hollingworth D, Herold KF, Kelly G, Mykhaylyk VB, Xiang J, Zhang D, Wallace BA, Hemmings HC.
bioRxiv [Preprint]. 2024 Nov 8:2024.11.04.621342.
doi: 10.1101/2024.11.04.621342.
PMID: 39574657.
Mechanisms of action of volatile general anesthetics (VAs) remain unclear.
Here: using the bacterial voltage-gated sodium channel (VGSC) NavMs from Magnetococcus marinus, study of the interaction with the VA sevoflurane, revealing multisite binding models.
First high-resolution structure of a VA bound to an ion channel.
The C-terminus of the multi-drug efflux pump EmrE prevents proton leak by gating transport
Merissa Brousseau, Da Teng, Nathan Thomas, Gregory A Voth, Katherine A Henzler-Wildman
bioRxiv 2024.11.21.624706;
doi: https://doi.org/10.1101/2024.11.21.624706
EmrE from E. coli can switch between different transport modes, affecting drug resistance and susceptibility.
Here: authors show that C-terminal tail = secondary gate to prevent proton leakage in the absence of substrates, with substrate binding unlocking this gate to enable transport.
Membranes
Direct lipid interactions control SARS-CoV-2 M protein conformational dynamics and virus assembly.
Dutta M, Dolan KA, Amiar S, Bass EJ, Sultana R, Voth GA, Brohawn SG, Stahelin RV.
bioRxiv [Preprint]. 2024 Nov 5:2024.11.04.620124.
doi: 10.1101/2024.11.04.620124.
PMID: 39574576.
M protein = most abundant structural membrane protein in coronaviruses transitions between two conformations, M short and M long.
Here: M interacts with Golgi-enriched anionic lipids, particularly ceramide-1-phosphate (C1P) => stabilization of the M short conformation and facilitates viral assembly.
Endogenous signaling lipids regulate M structure and support a model in which M short is stabilized in the early endomembrane system to organize other structural proteins prior to viral budding.
A tuneable minimal cell membrane reveals that two lipid species suffice for life.
Justice I, Kiesel P, Safronova N, von Appen A, Saenz JP.
Nat Commun. 2024 Nov 8;15(1):9679.
doi: 10.1038/s41467-024-53975-y.
PMID: 39516463.
Demonstration that a minimal two-component lipidome can sustain life.
Acyl chain diversity, rather than head group diversity, is shown to be critical for growth + heterochirality reduces fitness in these simple cells.
Cryo-electron tomography reveals how COPII assembles on cargo-containing membranes.
Pyle E, Miller EA, Zanetti G.
Nat Struct Mol Biol. 2024 Nov 7.
doi: 10.1038/s41594-024-01413-4. Epub ahead of print.
PMID: 39511455.
COPII complex (carriers with diverse cargo properties) => transport of newly synthesized proteins from the ER.
Here: reconstitution of COPII-coated vesicles using S. cerevisiae proteins and native membranes => cryoET => forms largely spherical vesicles and binds cargo directly.
Structural insights into the inner and outer coat layers highlight how COPII generates membrane curvature.
How Bacteria Establish and Maintain Outer Membrane Lipid Asymmetry.
Tan WB, Chng SS.
Annu Rev Microbiol. 2024 Nov;78(1):553-573.
doi: 10.1146/annurev-micro-032521-014507. Epub 2024 Nov 7.
PMID: 39270665.
Review of the mechanisms by which bacteria establish and sustain membrane asymmetry, including specialized lipid transport systems that place LPS and PLs in their correct leaflets, prevent PL mislocalization, and repair asymmetry defects.
Atherosclerotic Oxidized Lipids Affect Formation and Biophysical Properties of Supported Lipid Bilayers and Simulated Membranes.
Santa DE, Brown TP, Im W, Wittenberg NJ.
J Phys Chem B. 2024 Nov 18.
doi: 10.1021/acs.jpcb.4c05451. Epub ahead of print.
PMID: 39558641.
Oxidized PC, linked to atherosclerosis and cardiovascular diseases, alter the biophysical properties of lipid bilayers, including their thickness and structural integrity.
Here: using experimental and computational methods, authors show that oxPC-containing liposomes form supported lipid bilayers (SLBs) differently than nonoxidized liposomes (thinner membranes with defects as oxPC concentration increases).
Simulations => oxidized lipid tails bend into the hydrophilic regions, influencing membrane structure based on cholesterol content and protonation state.
Combining live cell fluorescence imaging with in situ cryo electron tomography sheds light on the septation process in Deinococcus radiodurans
L. Gaifas, J.P. Kleman, F. Lacroix, E. Schexnaydre, J. Trouve, C. Morlot, L. Sandblad, I. Gutsche, J. Timmins
bioRxiv 2024.11.18.624142;
doi: https://doi.org/10.1101/2024.11.18.624142
Deinococcus radiodurans employs a unique “sliding doors” mode of cell division (septa form from opposite sides with flat leading edges that fuse at mid-cell).
Here: using super-resolution fluorescence microscopy and cryoET, authors elucidate the bacterium’s complex cell envelope architecture and the molecular mechanisms driving its distinctive septal growth and closure.
Molecules
A molecular anion pump.
Shao B, Fu H, Aprahamian I.
Science. 2024 Aug 2;385(6708):544-549.
doi: 10.1126/science.adp3506. Epub 2024 Aug 1.
PMID: 39088617.
Study demonstrating an artificial receptor capable of mimicking ion transport against concentration gradients using light energy.
The trimeric hydrazone photoswitch-based receptor actively pumps chloride ions against a gradient in a dichloromethane membrane => its bistability and ON-OFF binding properties with differences of up to six orders of magnitude.
Methods
Computational engineering of water-soluble human potassium ion channels through QTY transformation.
Smorodina E, Tao F, Qing R, Yang S, Zhang S.
Sci Rep. 2024 Nov 15;14(1):28159.
doi: 10.1038/s41598-024-76603-7.
PMID: 39548172.
Structural bioinformatics to design QTY variants of potassium channels, substituting hydrophobic residues with hydrophilic ones, resulting in water-soluble proteinswhile preserving structural similarity and stability.
Protein-protein interaction and conformational change in the alpha-helical membrane transporter BtuCD-F in the native cellular envelope.
Joseph B.
Chembiochem. 2024 Nov 17:e202400858.
doi: 10.1002/cbic.202400858. Epub ahead of print.
PMID: 39551706.
Pulsed dipolar electron spin resonance spectroscopy, combined with Gd³⁺-nitroxide spin pairs, to observe the vitamin B12 importer BtuCD-F in its native cellular envelope, revealing a distinct conformational shift at the protein interface induced by vitamin B12.
Successful strategies for expression and purification of ABC transporters.
Berner B, Daoutsali G, Melén E, Remper N, Weszelovszká E, Rothnie A, Hedfalk K.
Biochim Biophys Acta Biomembr. 2024 Nov 11:184401.
doi: 10.1016/j.bbamem.2024.184401. Epub ahead of print.
PMID: 39537006.
Review summarizing strategies for successfully producing stable and functional ABC transporters from both prokaryotic and eukaryotic systems, with E. coli and HEK293 as most common host systems.
MPA-MutPred: a novel strategy for accurately predicting the binding affinity change upon mutation in membrane protein complexes.
Ridha F, Gromiha MM.
Brief Bioinform. 2024 Sep 23;25(6):bbae598.
doi: 10.1093/bib/bbae598.
PMID: 39550225.
Existing prediction methods for mutations that alter protein binding affinities are not tailored for MP complexes.
Here: MPA-MutPred, a novel method that combines linear and nonlinear models to predict mutation-induced changes in binding affinity (ΔΔG) in MP complexes.
Method validated through extensive testing + freely accessible.
Using deep learning and large protein language models to predict protein-membrane interfaces of peripheral membrane proteins.
Paranou D, Chatzigoulas A, Cournia Z.
Bioinform Adv. 2024 May 28;4(1):vbae078.
doi: 10.1093/bioadv/vbae078.
PMID: 39559823.
Available experimental data used and generate protein embeddings from two pLMs (ProtTrans and ESM) to train classifier models. Overall, the results demonstrate the first PoC study and potential of using deep learning and pLMs to predict protein-membrane interfaces for PMPs faster without the need for 3D structural data compared to existing tools.
NMR spectroscopy reveals insights into mechanisms of GPCR signaling.
Silva LO, Wijesekara AV, Eddy MT.
TIBS ”Technology of the Month”
Trends Biochem Sci. 2024 Nov 9:S0968-0004(24)00232-9.
doi: 10.1016/j.tibs.2024.10.007. Epub ahead of print.
PMID: 39523165.
NMR is a powerful technique used to study challenging MPs, including GPCRs. NMR provides detailed insights into a wide range of receptor properties, including ligand-stimulated signaling mechanisms and pathways, receptor–lipid and receptor–ligand interactions, and quantitative measurements of conformational exchange rates and receptor structure.
Microbio
Determination of Pseudomonas aeruginosa MexXY-OprM substrate profile in a major efflux knockout system reveals distinct antibiotic substrate classes
Logan Glenn Kavanaugh, Shraddha M. Hariharan, Graeme Leslie Conn
bioRxiv 2024.10.18.619101;
doi: https://doi.org/10.1101/2024.10.18.619101
Defining the substrates of RND systems is complicated by multiple systems in a single bacterial species.
Here: using a major efflux KO strain, authors developed a P. aeruginosa expressing MexXY-OprM in the absence of background efflux complexes.
=> 3 groups of potential substrates for MexXY-OprM: substrates, partial substrates, and nonsubstrates + definition of trimethoprim as a new substrate.
Miscellaneous
Enriched environment exposure accelerates rodent driving skills.
Crawford LE, Knouse LE, Kent M, Vavra D, Harding O, LeServe D, Fox N, Hu X, Li P, Glory C, Lambert KG.
Behav Brain Res. 2020 Jan 27;378:112309.
doi: 10.1016/j.bbr.2019.112309. Epub 2019 Oct 16.
PMID: 31629004.
or
Rats taught to drive tiny cars to lower their stress levels
In 2020, scientists taught rats to drive tiny cars, and the animals loved it. Now the researchers have extended their work to show how the anticipation of a good time can ramp up rats’ capacity for joy. Preliminary results suggest that animals who learnt to wait for their turn behind the wheel tested as more ‘optimistic’ in their thinking, performed better on cognitive tasks and were bolder in their problem-solving strategies.
From advisors to mentors: fostering supportive mentorship in academia.
Azarbad H, Laskowski R, Stoeger H, van Straalen NM.
Trends Microbiol. 2024 Nov 13:S0966-842X(24)00264-6.
doi: 10.1016/j.tim.2024.10.004. Epub ahead of print.
PMID: 39542816.
A supportive mentorship has long-lasting effects on shaping students’ personal and professional development. Here, authors outline important aspects of mentoring and indicators of good mentors, focusing on effective mutualistic interaction. Traditional academic advice should be expanded to include supportive group mentoring to foster future top scientific talent.
Adipose tissue retains an epigenetic memory of obesity after weight loss.
Hinte LC, Castellano-Castillo D, Ghosh A, Melrose K, Gasser E, Noé F, Massier L, Dong H, Sun W, Hoffmann A, Wolfrum C, Rydén M, Mejhert N, Blüher M, von Meyenn F.
Nature. 2024 Nov 18.
doi: 10.1038/s41586-024-08165-7. Epub ahead of print.
PMID: 39558077.
The body’s fat cells carry a ‘memory’ of obesity, even after weight loss. The memory is formed because obesity causes epigenetic changes in the cells, which seem to render them incapable of their normal function even when weight returns to healthy levels. The results suggest that people trying to slim down will often require long-term care to avoid weight regain.
‘Forever’ chemicals can be destroyed with clever chemistry – now test these techniques outside the lab.
Nature. 2024 Nov;635(8039):524.
doi: 10.1038/d41586-024-03753-z.
PMID: 39567794.
The carbon–fluorine (C–F) bond is one of the strongest in organic chemistry, and the reason why per- and polyfluoroalkyl substances (PFAS), which contain many of them, are called ‘forever chemicals’. PFAS have a myriad of uses, but they also require huge amounts of energy to break down, which is also hugely costly. Now two papers in Nature describe different low-energy ways to overcome the C–F bond using catalysts activated by visible light. A Nature editorial urges scientists to upscale these processes for real-world settings, and also advocates for updated regulation and for more research into safer alternatives.
‘A place of joy’: why scientists are joining the rush to Bluesky.
Mallapaty S.
Nature. 2024 Nov 21.
doi: 10.1038/d41586-024-03784-6. Epub ahead of print.
PMID: 39572670.
In the two weeks since the US presidential election, the platform has grown from close to 14 million users to nearly 21 million. Bluesky has broad appeal in large part because it looks and feels a lot like X (formerly known as Twitter), which became hugely popular with scientists, who used it to share research findings, collaborate and network. One estimate suggests that at least half a million researchers had Twitter profiles in 2022.
BTW BPM has also joined Bluesky !
Follow us here: @bpm7099.bsky.social