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Margeat, E.

Publications and source records attributed to Margeat, E..

10 recordsLinked to original sources

Distinct spatial organisation of Rho and RNA Polymerase in Salmonella cells

Rho is a conserved, ATP-dependent RNA translocase that terminates transcription at hundreds of sites across bacterial genomes. Although the molecular mechanism of Rho-dependent termination is well characterized, its spatial interplay with RNA polymerase (RNAP) within bacterial cells remains elusive. To address this question, we constructed intragenic, in-frame fusions inserting mCherry or sfGFP 48 amino acid residues downstream of the N-terminus of Rho in Salmonella. Strikingly, mCherry - but not sfGFP - renders the first 48 residues of Rho dispensable. Rho{Delta}48::mCherry is viable in single copy and exhibits wild-type termination activity in vitro, whereas the full-length Rho::sfGFP fusion, although viable, slows growth and shows strongly reduced activity. Structured illumination microscopy (SIM) revealed that, despite these functional differences, both constructs exhibit similar localisation patterns relative to fluorescently tagged RNAP in single cells. During exponential growth, both Rho and RNAP form discrete clusters, but with markedly distinct spatial organisations: RNAP clusters associate with the nucleoid, whereas Rho is distributed throughout the cell body. This spatial partitioning persists in stationary phase, where RNAP becomes diffusely associated with a compacted nucleoid while Rho accumulates at the cell periphery. The widespread distribution of Rho at cytoplasmic locations is unexpected and suggests participation in cellular functions beyond its canonical role in transcription termination.

microbiology↗

Triple labeling resolves a GPCR intermediate state by 3-color single molecule FRET

The correlation of individual conformational changes in dynamic protein complexes remains challenging as most structural methods rely on averaged information over large numbers molecules. Single molecule FRET is a powerful tool for monitoring such conformational changes. When performed using three distinct probes, it enables the correlation of domain movements by providing up to three simultaneous distance measurements with high temporal resolution. Nevertheless, a major challenge lies in the site-specific attachment of three probes to unique positions within the target protein. Here, we propose an orthogonal triple-labeling strategy that is not compromised by native, reactive amino acid functionalities. It combines genetic code expansion and biorthogonal labeling of two different non-canonical amino-acids with an enzymatic self-labeling SNAP tag. We demonstrate its application by establishment of a 3-color sensor on the human metabotropic glutamate receptor 2, a dimeric, multidomain G protein-coupled neuroreceptor, and describe a previously unknown conformational intermediate state using 3-color single molecule FRET.

biophysics↗

Single-stranded DNA drives sigma subunit loading onto RNA polymerase to unlock initiation-competent conformations

Initiation of transcription requires the formation of the "open" promoter complex (RPo). For this, the {sigma} subunit of bacterial RNA polymerase (RNAP) binds to the non-template strand of the -10 element sequence of promoters and nucleates DNA unwinding. This is accompanied by a cascade of conformational changes on RNAP the mechanics of which remains elusive. Here, using single-molecule Forster resonance energy transfer and cryo-electron microscopy, we explored the conformational landscape of RNAP from the human pathogen Mycobacterium tuberculosis upon binding to a single-stranded DNA fragment that includes the -10 element sequence (-10 ssDNA). We found that like the transcription activator RbpA, -10 ssDNA induced {sigma} subunit loading onto the DNA/RNA channels of RNAP. This triggered RNAP clamp closure and unswiveling that are required for RPo formation and RNA synthesis initiation. Our results reveal a mechanism of ssDNA-guided RNAP maturation and identify the {sigma} subunit as a regulator of RNAP conformational dynamics

molecular biology↗

Mechanosensitivity of an ABC Membrane Transporter Revealed by Single Molecule FRET and Activity Measurement

While mechanosensitive ion channels gating has been well documented, the effect of membrane mechanics, in particular membrane curvature, on the function of transporters remains elusive. Since conical shape transmembrane proteins locally deform membranes, conversely membrane bending could impact their conformations and their function. We tested this hypothesis using BmrA, a bacterial ABC exporter that exhibits large conformational changes upon ATP hydrolysis, switching between open and closed states with opposite V-shapes. After reconstitution in liposomes of different curvatures, and at two different temperatures, we showed that BmrA ATPase activity decreases by 2.9-fold when their diameter decreases from 125 to 29 nm. Moreover, using single-molecule FRET, we observed that the fraction of closed conformations is reduced in highly curved vesicles when adding ATP or non-hydrolysable AMP-PNP. Our results are well explained by a theoretical 2-states model including the effect of membrane mechanics on protein shape transition. Our work reveals that the functional cycle of conical transporters is curvature sensitive, to an extent depending on protein geometry. Significance StatementBiological membranes actively regulate protein function. While some ion channels are known to sense membrane tension, whether transporters also respond to mechanical cues was unknown. We show that the conical-shaped bacterial exporter BmrA is sensitive to membrane curvature, with both its activity and conformation landscape determined by the surrounding lipid bilayer. This reveals a previously unrecognized mechanism of mechanosensitivity, suggesting that membrane geometry and transporter shape are intrinsically coupled, providing a general principle of regulation across biological systems.

biophysics↗

Reliability and accuracy of single-molecule FRET studies for characterization of structural dynamics and distances in proteins

Single-molecule FRET (smFRET) has become an established tool to study biomolecular structure and dynamics in vitro and in live cells. We performed a worldwide blind study involving 19 labs to assess the uncertainty of FRET experiments for proteins with respect to the measured FRET efficiency histograms, determination of distances, and the detection and quantification of structural dynamics. Using two protein systems that undergo distinct conformational changes, we obtained an uncertainty of the FRET efficiency of less than {+/-} 0.06, corresponding to an interdye distance precision of [≤] 0.2 nm and accuracy of [≤] 0.5 nm. We further discuss the limits for detecting distance fluctuations with sensitivity down to [lsim] 10% of the Forster distance and provide guidelines on how to detect potential dye perturbations. The ability of smFRET experiments to simultaneously measure distances and avoid averaging of conformational dynamics slower than the fluorescence lifetime is unique for dynamic structural biology.

biophysics↗

Assembly mechanism and cryoEM structure of RecA recombination nucleofilaments from Streptococcus pneumoniae.

RecA-mediated Homologous Recombination (HR) is a key mechanism for genome maintenance and plasticity in bacteria. It proceeds through RecA assembly into a dynamic filament on ssDNA, the presynaptic filament, which mediates DNA homology search and ordered DNA strand exchange. Here, we combined structural, single molecule and biochemical approaches to characterize the ATP-dependent assembly mechanism of the presynaptic filament of RecA from Streptococcus pneumoniae (SpRecA), in comparison to the Escherichia coli RecA (EcRecA) paradigm. EcRecA polymerization on ssDNA is assisted by the Single-Stranded DNA Binding (SSB) protein, which unwinds ssDNA secondary structures that block EcRecA nucleofilament growth. We report that neither of the two paralogous pneumococcal SSBs could assist SpRecA polymerization on ssDNA. Instead, we found that the conserved RadA helicase promotes this SpRecA nucleofilamentation in an ATP-dependent manner. This allowed us to solve the atomic structure of such a long native SpRecA nucleopolymer by cryoEM stabilized with ATP{gamma}S. It was found to be equivalent to the crystal structure of the EcRecA filament with a marked difference in how RecA mediates nucleotide orientation in the stretched ssDNA. Then, our results show that SpRecA and EcRecA HR activities are different, in correlation with their distinct ATP-dependent ssDNA binding modes.

microbiology↗

Dissecting conformational rearrangements and allosteric modulation in metabotropic glutamate receptor activation

Selective allosteric modulators bear great potential to fine-tune neurotransmitter-induced brain receptor responses. Promising targets are metabotropic glutamate (mGlu) receptors, which are associated to different brain diseases. These multidomain class C GPCRs experience concerted structural rearrangements and rely on allosteric modulation of agonist action to be fully activated. Here we establish live cell compatible fluorescence labeling of mGlu2 by click chemistry through genetic code expansion. Using lanthanide resonance energy transfer, we establish multiple FRET sensors to monitor ligand effects on conformational changes in mGlu2 extracellular domain and subsequently dissect the underlying conformational states by smFRET. Using three distinct FRET sensors, we demonstrate that mGlu activation relies on a ligand-induced sampling of three conformational states. Orthosteric agonists act by promoting the closure of the mGlu2 ligand binding domains, leading to an equilibrium between an inactive intermediate and the active state. Allosteric modulator further push this equilibrium toward the active state, promoting and stabilizing the relative reorientation of the mGlu protomers. These results underline the complex and dynamic nature of such type of neuroreceptors, pointing out that ligands fine-tune activation by differentially acting on the equilibria between multiple states.

biophysics↗

Cryo-EM structure of the transcription termination factor Rho from Mycobacterium tuberculosis reveals mechanism of resistance to bicyclomycin

The bacterial Rho factor is a ring-shaped motor triggering genome-wide transcription termination and R-loop dissociation. Rho is essential in many species, including in Mycobacterium tuberculosis where rho gene inactivation leads to rapid death. Yet, the M. tuberculosis Rho [MtbRho] factor displays poor NTPase and helicase activities, and resistance to the natural Rho inhibitor bicyclomycin [BCM] that remain unexplained. Here, we address these unusual features by solving the cryo-EM structure of MtbRho at 3.3 [A] resolution, providing a new framework for future antibiotic development. The MtbRho hexamer is poised into a pre-catalytic, open-ringed state wherein specific contacts stabilize ATP in intersubunit ATPase pockets, thereby explaining the cofactor preference of MtbRho. We reveal a leucine-to-methionine substitution that creates a steric bulk in BCM binding cavities near the positions of ATP {gamma}-phosphates, and confers resistance to BCM at the expense of motor efficiency.

molecular biology↗

Single molecule analysis reveals positive allosteric modulators are required to stabilize the active state of a metabotropic glutamate receptor

Much hope in drug development comes from the discovery of positive allosteric modulators (PAM) that display target subtype selectivity, and act by increasing agonist potency and efficacy. How such compounds can allosterically influence agonist action remains unclear. Metabotropic glutamate receptors (mGlu) are G protein-coupled receptors that represent promising targets for brain diseases, and for which PAMs acting in the transmembrane domain have been developed. Here, we explore the effect of a PAM on the structural dynamics of mGlu2 in optimized detergent micelles using single molecule FRET at submillisecond timescales. We show that glutamate only partially stabilizes the extracellular domains in the active state. Full activation is only observed in the presence of a PAM or the Gi protein. Our results provide important insights on the role of allosteric modulators in mGlu activation, by stabilizing the active state of a receptor that is otherwise rapidly oscillating between active and inactive states.

biophysics↗

Accurate Determination of Human CPR Conformational Equilibrium by smFRET using Dual Orthogonal Non-Canonical Amino Acid Labeling

Conjugation of fluorescent dyes to proteins - a prerequisite for the study of conformational dynamics by single molecule Forster resonance energy transfer (smFRET) - can lead to substantial changes of the dyes photophysical properties, ultimately biasing the quantitative determination of inter-dye distances. In particular the popular cyanine dyes and their derivatives, which are by far the most used dyes in smFRET experiments, exhibit such behavior. To overcome this, a general strategy to site-specifically equip proteins with FRET pairs by chemo-selective reactions using two distinct non-canonical amino acids simultaneously incorporated through genetic code expansion in Escherichia coli was developed. Applied to human NADPH- cytochrome P450 reductase (CPR), the importance of homogenously labeled samples for accurate determination of FRET efficiencies was demonstrated. Furthermore, the effect of NADP+ on the ionic strength dependent modulation of the conformational equilibrium of CPR was unveiled. Given its generality and accuracy, the presented methodology establishes a new benchmark to decipher complex molecular dynamics on single molecules.

biochemistry↗