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Neurotransmitter release is triggered by a calcium- induced rearrangement in the Synaptotagmin-1/SNARE complex primary interface

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2024年第42期121卷 e2409636121页

作者： Toulme, Estelle Lazaro, Andrea Salazar Trimbuch, Thorsten Rizo, Josep Rosenmund, Christian Charite Univ Med Berlin Inst Neurophysiol D-10117 Berlin Germany Free Univ Berlin D-10117 Berlin Germany Humboldt Univ D-10117 Berlin Germany NeuroCure Cluster Excellence D-10117 Berlin Germany Univ Texas Southwestern Med Ctr Dept Biophys Dallas TX 75390 USA Univ Texas Southwestern Med Ctr Dept Biochem Dallas TX 75390 USA Univ Texas Southwestern Med Ctr Dept Pharmacol Dallas TX 75390 USA

The Ca2+ sensor synaptotagmin-1 (Syt1) triggers neurotransmitter release together with the neuronal sensitive factor attachment protein receptor (SNARE) complex formed by syntaxin-1, SNAP25, and synaptobrevin. Moreover, Syt1 increases synaptic vesicle (SV) priming and impairs spontaneous vesicle release. The Syt1 C2B domain binds to the SNARE complex through a primary interface via two regions (I and II), but how exactly this interface mediates distinct functions of Syt1 and the mechanism underlying Ca2+ triggering of release are unknown. Using mutagenesis and electrophysiological experiments, we show that region II is functionally and spatially subdivided: Binding of C2B domain arginines to SNAP- 25 acidic residues at one face of region II is crucial for Ca2+- evoked release but not for vesicle priming or clamping of spontaneous release, whereas other SNAP- 25 and syntaxin-1 acidic residues at the other face mediate priming and clamping of spontaneous release but not evoked release. Mutations that disrupt region I impair the priming and clamping functions of Syt1 while, strikingly, mutations that enhance binding through this region increase vesicle priming and clamping of spontaneous release, but strongly inhibit evoked release and vesicle fusogenicity. These results support previous findings that the primary interface mediates the functions of Syt1 in vesicle priming and clamping of spontaneous release and, importantly, show that Ca2+ triggering of release requires a rearrangement of the primary interface involving dissociation of region I, while region II remains bound. Together with biophysical studies presented in [K. Jaczynska etal., bioRxiv [Preprint] (2024). https://doi. org/10.1101/2024.06.17.599417 (Accessed 18 June 2024)], our data suggest a model whereby this rearrangement pulls the SNARE complex to facilitate fast SV fusion.

关键词： neurotransmitter release SNAREs synaptotagmin synaptic vesicle fusion structure-function

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Human brain dynamics are shaped by rare long- range connections over and above cortical geometry

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2025年第1期122卷 e2415102122页

作者： Vohryzek, Jakub Sanz-Perl, Yonatan Kringelbach, Morten L. Deco, Gustavo Univ Pompeu Fabra Ctr Brain & Cognit Dept Informat & Commun Technol Computat Neurosci Grp Barcelona 08018 Spain Univ Oxford Linacre Coll Ctr Eudaimonia & Human Flourishing Dept Psychiat Oxford OX3 9BX England Univ Oxford Dept Psychiat Oxford OX3 7JX England Aarhus Univ Ctr Mus Brain Dept Clin Med DK-8000 Aarhus Denmark Inst Catalana Recerca & Estudis Avancats Barcelona 08010 Spain

A fundamental topological principle is that the container always shapes the content. In neuroscience, this translates into how the brain anatomy shapes brain dynamics. From neuroanatomy, the topology of the mammalian brain can be approximated by local connectivity, accurately described by an exponential distance rule (EDR). The compact, folded geometry of the cortex is shaped by this local connectivity, and the geometric harmonic modes can reconstruct much of the functional dynamics. However, this ignores the fundamental role of the rare long- range (LR) cortical connections, crucial for improving information processing in the mammalian brain, but not captured by local cortical folding and geometry. Here, we show the superiority of harmonic modes combining rare LR connectivity with EDR (EDR+LR) in capturing functional dynamics (specifically LR functional connectivity and task- evoked brain activity) compared to geometry and EDR representations. Importantly, the orchestration of dynamics is carried out by a more efficient manifold made up of a low number of fundamental EDR+LR modes. Our results show the importance of rare LR connectivity for capturing the complexity of functional brain activity through a low- dimensional manifold shaped by fundamental EDR+LR modes.

关键词： structure-function brain connectivity brain geometry fMRI harmonic decomposition

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Hsp90: Bringing it all together

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CELL STRESS & CHAPERONES 2025年第1期30卷 69-79页

作者： Karras, Georgios Ioannis Colombo, Giorgio Kravats, Andrea N. Univ Texas MD Anderson Canc Ctr Dept Genet Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr UTHealth Houston Grad Sch Biomed Sci Genet & Epigenet Grad Program Houston TX 77030 USA Univ Pavia Dept Chem Pavia Italy Miami Univ Dept Chem & Biochem Oxford OH 45056 USA

Heat-shock protein 90 (Hsp90) is an ancient and multifaceted protein-folding machine essential for most organisms. The past 40 years have uncovered remarkable complexity in the regulation and function of Hsp90, which dwarfs most other machines in the cell in sophistication. Here, we propose four analogies to illustrate Hsp90's sophistication: a multifunctional Swiss Army knife, an automobile engine and its controls, a switchboard acting as a hub and directing signals, and an orchestra conductor setting the tempo of a symphony. Although each of these analogies represents some key Hsp90 activities, none of them captures the entirety of Hsp90's complexity. Together, these roles enable Hsp90 to support both homeostasis and differentiation, both cellular stability and adaptability. At the 11th International Conference on the Hsp90 Chaperone Machine, the consensus was that to understand this major guardian of proteostasis, we need to study how the many facets of Hsp90's function influence each other. We hope that these analogies will help to conceptually integrate the many roles of Hsp90 in proteostasis and help the field develop the practical applications of Hsp90 modulators.

关键词： Hsp90 Proteostasis structure-function Evolution Modulators

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Influence of Arabinan Fine structure, Galacturonan Backbone Length, and Degree of Esterification on the Emulsifying Properties of Acid-Extracted Sugar Beet Pectins

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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023年第4期71卷 2105-2112页

作者： Eichhoefer, Hendrik Bindereif, Benjamin Karbstein, Heike Petra Bunzel, Mirko Schaaf, Ulrike Sabine van der Wefers, Daniel Karlsruhe Inst Technol KIT Inst Proc Engn Life Sci Food Proc Engn D-76131 Karlsruhe Germany Martin Luther Univ Halle Wittenberg Inst Chem Div Food Chem D-06120 Halle Germany Karlsruhe Inst Technol KIT Inst Appl Biosci Dept Food Chem & Phytochemistry D-76131 Karlsruhe Germany

Sugar beet pectins (SBPs) are known for their emulsifying properties, but it is yet unknown which structural elements are most important for functionality. Recent results indicated that the arabinose content has a decisive influence, but the approach applied did not allow causality to be established. In this study, a mostly intact SBP was selectively modified and the obtained pectins were analyzed for their molecular structure and their emulsifying properties. De-esterification only resulted in a moderate increase in droplet size. The length of the pectin backbone only influenced the emulsifying properties when the homogalacturonan backbone was cleaved to a higher extent. By using different arabinan-modifying enzymes, it was demonstrated that both higher portions and chain lengths of arabinans positively influence the emulsifying properties of SBPs. Therefore, we were able to refine the structure- function relationships for acid-extracted SBPs, which can be used to optimize extraction conditions.

关键词： enzymatic modification emulsion stabilization structure-function acetylation methylation

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Residue alterations within a conserved hydrophobic pocket influence light, oxygen, voltage photoreceptor dark recovery

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PHOTOCHEMICAL & PHOTOBIOLOGICAL SCIENCES 2023年第4期22卷 713-727页

作者： Hemmer, Stefanie Schulte, Marianne Knieps-Gruenhagen, Esther Granzin, Joachim Willbold, Dieter Jaeger, Karl-Erich Batra-Safferling, Renu Panwalkar, Vineet Krauss, Ulrich Forschungszentrum Julich GmbH Heinrich Heine Univ Dusseldorf Inst Mol Enzymtechnol D-52425 Julich Germany Forschungszentrum Julich IBG Biotechnol 1 D-52425 Julich Germany Forschungszentrum Julich IBI Struct Biochem 7 D-52425 Julich Germany Heinrich Heine Univ Dusseldorf Inst Phys Biol D-40225 Dusseldorf Germany Forschungszentrum Julich JuStruct Julich Ctr Struct Biol D-52428 Julich Germany Biozent Univ Basel CH-4056 Basel Switzerland

Light, oxygen, voltage (LOV) photoreceptors are widely distributed throughout all kingdoms of life, and have in recent years, due to their modular nature, been broadly used as sensor domains for the construction of optogenetic tools. For understanding photoreceptor function as well as for optogenetic tool design and fine-tuning, a detailed knowledge of the photophysics, photochemistry, and structural changes underlying the LOV signaling paradigm is instrumental. Mutations that alter the lifetime of the photo-adduct signaling state represent a convenient handle to tune LOV sensor on/off kinetics and, thus, steady-state on/off equilibria of the photoreceptor (or optogenetic switch). Such mutations, however, should ideally only influence sensor kinetics, while being benign with regard to the nature of the structural changes that are induced by illumination, i.e., they should not result in a disruption of signal transduction. In the present study, we identify a conserved hydrophobic pocket for which mutations have a strong impact on the adduct-state lifetime across different LOV photoreceptor families. Using the slow cycling bacterial short LOV photoreceptor PpSB1-LOV, we show that the I48T mutation within this pocket, which accelerates adduct rupture, is otherwise structurally and mechanistically benign, i.e., light-induced structural changes, as probed by NMR spectroscopy and X-ray crystallography, are not altered in the variant. Additional mutations within the pocket of PpSB1-LOV and the introduction of homologous mutations in the LOV photoreceptor YtvA of Bacillus subtilis and the Avena sativa LOV2 domain result in similarly altered kinetics. Given the conserved nature of the corresponding structural region, the here identified mutations should find application in dark-recovery tuning of optogenetic tools and LOV photoreceptors, alike.

关键词： Photoreceptor structure-function Photocycle kinetics Signaling Optogenetics

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Red Rubiscos and opportunities for engineering green plants

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JOURNAL OF EXPERIMENTAL BOTANY 2023年第2期74卷 520-542页

作者： Oh, Zhen Guo Askey, Bryce Gunn, Laura H. Cornell Univ Sch Integrat Plant Sci Plant Biol Sect Ithaca NY 14850 USA Uppsala Univ Dept Cell & Mol Biol S-75124 Uppsala Sweden

Nature's vital, but notoriously inefficient, CO2-fixing enzyme Rubisco often limits the growth of photosynthetic organisms including crop species. Form I Rubiscos comprise eight catalytic large subunits and eight auxiliary small subunits and can be classified into two distinct lineages-'red' and 'green'. While red-type Rubiscos (Form IC and ID) are found in rhodophytes, their secondary symbionts, and certain proteobacteria, green-type Rubiscos (Form IA and IB) exist in terrestrial plants, chlorophytes, cyanobacteria, and other proteobacteria. Eukaryotic red-type Rubiscos exhibit desirable kinetic properties, namely high specificity and high catalytic efficiency, with certain isoforms outperforming green-type Rubiscos. However, it is not yet possible to functionally express a high-performing red-type Rubisco in chloroplasts to boost photosynthetic carbon assimilation in green plants. Understanding the molecular and evolutionary basis for divergence between red- and green-type Rubiscos could help us to harness the superior CO2-fixing power of red-type Rubiscos. Here we review our current understanding about red-type Rubisco distribution, biogenesis, and sequence-structure, and present opportunities and challenges for utilizing red-type Rubisco kinetics towards crop improvements. We present a review of red- and green-type Rubisco functional and regulatory divergence, and how these present both challenges and opportunities to boost photosynthetic carbon assimilation in agricultural plants.

关键词： Carboxylation photosynthesis plastome protein engineering Rubisco structure-function

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Efficacy and accuracy of artificial intelligence to overlay multimodal images from different optical instruments in patients with retinitis pigmentosa

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CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY 2023年第5期51卷 446-452页

作者： Yassin, Shaden H. Wang, Yiqian Freeman, William R. Heinke, Anna Walker, Evan Nguyen, Truong Bartsch, Dirk-Uwe G. An, Cheolhong Borooah, Shyamanga Univ Calif San Diego Shiley Eye Inst Jacobs Retina Ctr La Jolla CA USA Univ Calif San Diego Dept Elect & Comp Engn La Jolla CA USA Univ Calif San Diego Shiley Eye Inst Retinal Div Ophthalmol 9415 Campus Point Dr La Jolla CA 92093 USA

BackgroundRetinitis pigmentosa (RP) represents a group of progressive, genetically heterogenous blinding diseases. Recently, relationships between measures of retinal function and structure are needed to help identify outcome measures or biomarkers for clinical trials. The ability to align retinal multimodal images, taken on different platforms, will allow better understanding of this relationship. We investigate the efficacy of artificial intelligence (AI) in overlaying different multimodal retinal images in RP patients. MethodsWe overlayed infrared images from microperimetry on near-infra-red images from scanning laser ophthalmoscope and spectral domain optical coherence tomography in RP patients using manual alignment and AI. The AI adopted a two-step framework and was trained on a separate dataset. Manual alignment was performed using in-house software that allowed labelling of six key points located at vessel bifurcations. Manual overlay was considered successful if the distance between same key points on the overlayed images was <= 1/2 degrees. ResultsFifty-seven eyes of 32 patients were included in the analysis. AI was significantly more accurate and successful in aligning images compared to manual alignment as confirmed by linear mixed-effects modelling (p < 0.001).A receiver operating characteristic analysis, used to compute the area under the curve of the AI (0.991) and manual (0.835) Dice coefficients in relation to their respective 'truth' values, found AI significantly more accurate in the overlay (p < 0.001). ConclusionAI was significantly more accurate than manual alignment in overlaying multimodal retinal imaging in RP patients and showed the potential to use AI algorithms for future multimodal clinical and research applications.

关键词： artificial intelligence microperimetry retinitis pigmentosa spectral domain optical coherence tomography structure-function

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Structural and dynamic determinants for highly selective RET kinase inhibition reveal cryptic druggability

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JOURNAL OF ADVANCED RESEARCH 2023年 45卷 87-100页

作者： Shehata, Moustafa A. Contreras, Julia Martin-Hurtado, Ana Froux, Aurane Mohamed, Hossam Taha El-Sherif, Ahmed A. Plaza-Menacho, Ivan Spanish Natl Canc Res Ctr CNIO Struct Biol Programme Kinases Prot Phosphorylat & Canc Grp Madrid 28029 Spain Cairo Univ Fac Sci Chem Dept Giza 12613 Egypt Cairo Univ Fac Sci Zool Dept Giza 12613 Egypt October Univ Modern Sci & Arts Fac Biotechnol Giza 12451 Egypt

Introduction: The structural and dynamic determinants that confer highly selective RET kinase inhibition are poorly understood. Objectives: To explore the druggability landscape of the RET active site in order to uncover structural and dynamic vulnerabilities that can be therapeutically ***: We apply an integrated structural, computational and biochemical approach in order to explore the druggability landscape of the RET active ***: We demonstrate that the that the druggability landscape of the RET active site is determined by the conformational setting of the ATP-binding (P-) loop and its coordination with the aC helix. Open and intermediate P-loop structures display additional druggable vulnerabilities within the active site that were not exploited by first generation RET inhibitors. We identify a cryptic pocket adjacent to the cat-alytic lysine formed by K758, L760, E768 and L772, that we name the post-lysine pocket, with higher druggability potential than the adenine-binding site and with important implications in the regulation of the phospho-tyrosine kinase activity. Crystal structure and simulation data show that the binding mode of highly-selective RET kinase inhibitors LOXO-292 and BLU-667 is controlled by a synchronous open P-loop and aC-in configuration that allows accessibility to the post-lysine pocket. Molecular dynamics simulations show that these inhibitors efficiently occupy the post-lysine pocket with high sta-bility through the simulation time-scale (300 ns), with both inhibitors forming hydrophobic contacts fur-ther stabilized by pi-cation interactions with the catalytic K758. Engineered mutants targeting the post -lysine pocket impact on inhibitor binding and sensitivity, as well as RET tyrosine kinase ***: The identification of the post-lysine pocket as a new druggable vulnerability in the RET kinase and its exploitation by second generation RET inhibitors have important implications for future drug desig

关键词： Protein kinases Oncogene structure-function Targeted-therapies Drug-discovery

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Cortical microstructural gradients capture memory network reorganization in temporal lobe epilepsy

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BRAIN 2023年第9期146卷 3923-3937页

作者： Royer, Jessica Lariviere, Sara Rodriguez-Cruces, Raul Cabalo, Donna Gift Tavakol, Shahin Auer, Hans Ngo, Alexander Park, Bo-yong Paquola, Casey Smallwood, Jonathan Jefferies, Elizabeth Caciagli, Lorenzo Bernasconi, Andrea Bernasconi, Neda Frauscher, Birgit Bernhardt, Boris C. McGill Univ Montreal Neurol Inst & Hosp Multimodal Imaging & Connectome Anal Lab Montreal PQ H3A 2B4 Canada McGill Univ Montreal Neurol Inst & Hosp Analyt Neurophysiol Lab Montreal PQ H3A 2B4 Canada Inha Univ Dept Data Sci Incheon 22212 South Korea Inst Basic Sci Ctr Neurosci Imaging Res Suwon 34126 South Korea Forschungszentrum Julich Multiscale Neuroanat Lab INM 1 D-52425 Julich Germany Queens Univ Dept Psychol Kingston ON K7L 3N6 Canada Univ York Dept Psychol York YO10 5DD England Univ Penn Dept Bioengn Philadelphia PA 19104 USA McGill Univ Montreal Neurol Inst & Hosp Neuroimaging Epilepsy Lab Montreal PQ H3A 2B4 Canada 3801 Rue Univ Montreal PQ H3A 2B4 Canada

Temporal lobe epilepsy (TLE), one of the most common pharmaco-resistant epilepsies, is associated with pathology of paralimbic brain regions, particularly in the mesiotemporal lobe. Cognitive dysfunction in TLE is frequent, and particularly affects episodic memory. Crucially, these difficulties challenge the quality of life of patients, sometimes more than seizures, underscoring the need to assess neural processes of cognitive dysfunction in TLE to improve patient management. Our work harnessed a novel conceptual and analytical approach to assess spatial gradients of microstructural differentiation between cortical areas based on high-resolution MRI analysis. Gradients track region-to-region variations in intracortical lamination and myeloarchitecture, serving as a system-level measure of structural and functional reorganization. Comparing cortex-wide microstructural gradients between 21 patients and 35 healthy controls, we observed a reorganization of this gradient in TLE driven by reduced microstructural differentiation between paralimbic cortices and the remaining cortex with marked abnormalities in ipsilateral temporopolar and dorsolateral prefrontal regions. Findings were replicated in an independent cohort. Using an independent post-mortem dataset, we observed that in vivo findings reflected topographical variations in cortical cytoarchitecture. We indeed found that macroscale changes in microstructural differentiation in TLE reflected increased similarity of paralimbic and primary sensory/motor regions. Disease-related transcriptomics could furthermore show specificity of our findings to TLE over other common epilepsy syndromes. Finally, microstructural dedifferentiation was associated with cognitive network reorganization seen during an episodic memory functional MRI paradigm and correlated with interindividual differences in task accuracy. Collectively, our findings showing a pattern of reduced microarchitectural differentiation between paralimbic regions a

关键词： epilepsy neuroimaging memory microstructure structure-function

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Structural lessons on bacterial secretins

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BIOCHIMIE 2023年 205卷 110-116页

作者： Barbat, Brice Douzi, Badreddine Voulhoux, Rome Aix Marseille Univ LCB UMR7283 CNRS IMM F-13009 Marseille France Univ Lorraine INRAE DynAM F-54000 Nancy France Aix Marseille Univ LCB UMR7283 CNRS IMM 31 Ch J Aiguier F-13009 Marseille France Aix Marseille Univ LCB UMR7283 CNRS IMM 31Ch J Aiguier F-13009 Marseille France

To exchange and communicate with their surroundings, bacteria have evolved multiple active and passive mechanisms for trans-envelope transport. Among the pore-forming complexes found in the outer membrane of Gram-negative bacteria, secretins are distinctive homo-oligomeric channels dedi-cated to the active translocation of voluminous structures such as folded proteins, assembled fibers, virus particles or DNA. Members of the bacterial secretin family share a common cylinder-shaped structure with a gated pore-forming part inserted in the outer membrane, and a periplasmic channel connected to the inner membrane components of the corresponding nanomachine. In this mini-review, we will present what recently determined 3D structures have told us about the mechanisms of translocation through secretins of large substrates to the bacterial surface or in the extracellular milieu.(c) 2022 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.

关键词： Bacterial secretin Beta-barrel Outer membrane Cryo-EM structure-function

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