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Structural lessons on bacterial secretins

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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Regulation of alanine racemase activity by carboxylates and the d-type substrate d-alanine

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FEBS JOURNAL 2023年第11期290卷 2954-2967页

作者： Shimizu-Ibuka, Akiko Sato, Aoi Ichimura, Hikaru Hiraga, Haruna Nakayama, Shiori Nishiwaki, Toshikazu Niigata Univ Pharm & Appl Life Sci Dept Appl Life Sci Niigata Japan Kanagawa Univ Fac Sci Dept Biol Sci 2946 Tsuchiya Hiratsuka Kanagawa 2591293 Japan Niigata Agr Res Inst Food Res Ctr Kamo Niigata Japan

Alanine racemases (ALRs) are essential for d-alanine (d-Ala) production in bacteria, and many ALRs have a conserved carbamylated lysine residue in the active site. Although short-chain carboxylates inhibit ALRs harbouring this lysine residue as substrate analogues, in an ALR variant with an alanine residue at this position, carboxylates behave as activators;however, this activation mechanism remains unclear. Here, we performed kinetic and structural analyses of U1ALR, an ALR from Latilactobacillus sakei UONUMA harbouring a glycine residue (Gly134) in the site of the carbamylated lysine residue. U1ALR was activated by various carboxylates and also by a G134K mutation, both of which caused a significant decrease in K-m, indicating an increase in substrate affinity. The U1ALR crystal structure revealed the presence of an acetate molecule bound in a position and at an orientation resembling the conformation of the carbamylated lysine side chain observed in the structures of other ALRs. These results suggest a regulatory mechanism for U1ALR activity involving two carboxylate-binding sites: one with high affinity near Gly134, where an acetate molecule is observed in the crystal structure and carboxylate binding results in enzyme activation;the other is the substrate-binding site, where carboxylate binding inhibits enzyme activity. Furthermore, we observed no carboxylate/G134K-mediated activation in the presence of d-Ala at high concentrations, implying that d-Ala also exhibits low-affinity binding in the first carboxylate-binding site and prevents carboxylate/G134K-induced activation. Such regulation of enzyme activity by carboxylates and d-Ala may be ubiquitous in many ALRs from lactic acid bacteria sharing the same sequence characteristics.

关键词： cloning crystal structure enzyme kinetics structure-function substrate recognition

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Comparing Generalized Estimating Equation and Linear Mixed Effects Model for Estimating Marginal Association with Bivariate Continuous Outcomes

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OPHTHALMIC EPIDEMIOLOGY 2023年第3期30卷 307-316页

作者： Li, Mingyi Kong, Xiangrong Johns Hopkins Bloomberg Sch Publ Hlth Dept Epidemiol Baltimore MD 21205 USA Johns Hopkins Sch Med Wilmer Eye Inst Baltimore MD USA Johns Hopkins Bloomberg Sch Publ Hlth Dept Biostat Baltimore MD USA Johns Hopkins Bloomberg Sch Publ Hlth Dept Hlth Behav & Soc Baltimore MD USA

Purpose Both linear regression with generalized estimating equations (GEE) and linear mixed-effects models (LMEM) can be used to estimate the marginal association of an exposure with clustered continuous outcomes. This study compares their performance for bivariate continuous outcomes which are common in eye studies. Methods Parametric and non-parametric simulations were used to compare the GEE models including independent, exchangeable, and unstructured working correlation structures and LMEM including random intercept only and random intercept and slope models in R and SAS. Data generation referenced the data distributions from a real-world study for estimating ocular structure-visual function relationships in patients with retinitis pigmentosa. Results From both parametric and non-parametric simulations, comparing the random intercept LMEM and GEE exchangeable model, bias was similar;coverage probability of the 95% confidence interval (CI) from the random intercept LMEM was often closer to 95%, especially when the sample size was small;the power for testing the association of the exposure was higher from the GEE exchangeable model, but its type-I error rate might be inflated especially when the sample size was small. The type-I error rate from the random intercept LMEM was closer to 0.05, but it might be under 0.05 and coverage probability might be over 95%. The GEE independent model performed worst and the LMEM with both random intercept and slope might not converge. Conclusion To estimate marginal exposure-outcome association with bivariate continuous outcomes, the random intercept LMEM may be preferred. It has the best coverage probability of 95% CI and is the only model with correct type-I error rates in this study. However, it may have low power and overly wide CI in studies with small sample size or low inter-eye correlation.

关键词： structure-function correlated data analysis clinical trial design FIGHT-RP study retinitis pigmentosa

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Disruption of structure-function coupling in the schizophrenia connectome

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NEUROIMAGE-CLINICAL 2014年 4卷 779-787页

作者： Cocchi, Luca Harding, Ian H. Lord, Anton Pantelis, Christos Yucel, Murat Zalesky, Andrew Univ Queensland Queensland Brain Inst St Lucia Qld Australia Univ Melbourne Melbourne Neuropsychiat Ctr Melbourne Vic Australia Melbourne Hlth Melbourne Vic Australia QIMR Berghofer Med Res Inst Brisbane Qld Australia Monash Univ Monash Biomed Imaging Monash Clin & Imaging Neurosci Clayton Vic 3800 Australia Monash Univ Sch Psychol Sci Clayton Vic 3800 Australia Univ Melbourne Melbourne Sch Engn Melbourne Vic Australia

Neuroimaging studies have demonstrated that the phenomenology of schizophrenia maps onto diffuse alterations in large-scale functional and structural brain networks. However, the relationship between structural and functional deficits remains unclear. To answer this question, patients with established schizophrenia and matched healthy controls underwent resting-state functional and diffusion weighted imaging. The network-based statistic was used to characterize between-group differences in whole-brain functional connectivity. Indices of white matter integrity were then estimated to assess the structural correlates of the functional alterations observed in patients. Finally, group differences in the relationship between indices of functional and structural brain connectivity were determined. Compared to controls, patients with schizophrenia showed decreased functional connectivity and impaired white matter integrity in a distributed network encompassing frontal, temporal, thalamic, and striatal regions. In controls, strong interregional coupling in neural activity was associated with well-myelinated white matter pathways in this network. This correspondence between structure and function appeared to be absent in patients with schizophrenia. In two additional disrupted functional networks, encompassing parietal, occipital, and temporal cortices, the relationship between function and structure was not affected. Overall, results from this study highlight the importance of considering not only the separable impact of functional and structural connectivity deficits on the pathoaetiology of schizophrenia, but also the implications of the complex nature of their interaction. More specifically, our findings support the core nature of fronto-striatal, fronto-thalamic, and fronto-temporal abnormalities in the schizophrenia connectome. (C) 2014 The Authors. Published by Elsevier Inc.

关键词： Brain connectivity fMRI Diffusion DTI Psychosis Resting-state structure-function

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Molecular dynamics analysis of the structural properties of the transglutaminases of Kutzneria albida and Streptomyces mobaraensis

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COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL 2022年 20卷 3924-3934页

作者： Giordano, Deborah Langini, Cassiano Caflisch, Amedeo Marabotti, Anna Facchiano, Angelo Inst Food Sci Natl Res Council Via Roma 64 I-83100 Avellino Italy Univ Zurich Dept Biochem Winterthurerstr 190 CH-8057 Zurich Switzerland Univ Salerno Dept Chem & Biol A Zambelli Via Giovanni Paolo II 132 I-84084 Fisciano SA Italy

The microbial transglutaminase (TGase) from Streptomyces mobaraensis (MTGase) is widely used for industrial applications. However, in the last decades, TGases from other bacteria have been described. We focused our attention on TGase, from Kutzneria albida (KalbTGase), recently characterized as more selective than MTGase and proposed for applications in drug delivery. By comparison of the crystallo-graphic structures, the volume of the catalytic site results smaller in KalbTGase. We compared KalbTGase and MTGase structural flexibility by molecular dynamics (MD) simulations at different conditions. KalbTGase is more rigid than MTGase at 300 K, but the catalytic site has a preserved conformation in both structures. Preliminary studies at higher temperatures suggest that KalbTGase acquires enhanced conformational flexibility far from the active site region. The volume of the catalytic active site pocket of KalbTGase at room temperature is smaller than that of MTGase, and decreases at 335 K, remaining stable after further temperature increase. On the contrary, in MTGase the pocket volume continues to decrease as the temperature increases. Overall, the results of our study suggest that at room temperature the enhanced specificity of KalbTGase could be related to a more closed catalytic pocket and lower flexibility than MTGase. Moreover, by preliminary results at higher temperature, KalbTGase structural flexibility suggests an adaptability to different substrates not recognized at room temperature. Lower adaptability of MTGase at higher temperature with a reduction of the catalytic pocket, instead, suggests a reduction of its activity. (c) 2022 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.

关键词： Acyltransferase Transglutaminase Protein flexibility structure-function Computational biology Bioinformatics

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In asthma positive phase III slopes can result from structural heterogeneity of the bronchial tree

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JOURNAL OF APPLIED PHYSIOLOGY 2022年第4期132卷 947-955页

作者： Verbanck, Sylvia A. B. Foy, Brody H. Vrije Univ Brussel VUB Univ Hosp UZ Brussel Resp Div Brussels Belgium Massachusetts Gen Hosp Ctr Syst Biol Boston MA 02114 USA Massachusetts Gen Hosp Dept Pathol Boston MA 02114 USA Harvard Med Sch Dept Syst Biol Boston MA 02115 USA

We have previously identified bronchial generations 5-7 as the locus of maximum contribution to the convective portion of the phase III slope in computed tomography (CT)-based lung models of patients with asthma. In the present study, we examined how phase III slope is generated locally, by specifically interrogating at individual branch points, the necessary condition for a phase III slope to occur: some degree of convective flow sequencing between any two daughter branches that have a heterogeneity in gas washout concentration between them. Flow sequencing at individual branch points showed a wide range of values, including branch points where flow sequencing was such that phase III slopes were negative locally. Yet, the net effect in the 24 bronchial trees that we studied was that flow sequencing between pairs of less and better ventilated units most frequently drove positive phase III slopes in generations 5-7. By investigating the link of local flow sequencing between any two daughter branches to the corresponding heterogeneity of mechanical lung properties, heterogeneity of compliance was seen to be a major determinant of flow sequencing. In these bronchial structures, compliance heterogeneity was essentially brought about by volume asymmetry resulting from terminating pathways within the three-dimensional (3-D) confines of the lung contours. We conclude that the serial and parallel combination of lung mechanical properties at individual branch points in an asymmetrical branching network generates flow sequencing in mid-range conductive airways, leading to a positive at-mouth phase Ill slope. NEW & NOTEWORTHY Conceptually, the simplest way to obtain a sloping phase III during a washout exhalation is when there is convective flow sequencing between two lung units, such that the better ventilated unit contributes relatively more to exhaled flow at the beginning of phase III in the exhalation. Here, we show how compliance heterogeneity across the serial and paral

关键词： asthma computational lung model phase III slope structure-function ventilation heterogeneity

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The engineering challenges and opportunities when designing potent ionizable materials for the delivery of ribonucleic acids

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EXPERT OPINION ON DRUG DELIVERY 2022年第12期19卷 1650-1663页

作者： Lau, Yan Ming Anson Pang, Janice Tilstra, Grayson Couture-Senecal, Julien Khan, Omar F. Univ Toronto Inst Biomed Engn Toronto ON Canada Univ Toronto Dept Immunol Toronto ON Canada

IntroductionIonizable lipids are critical components in lipid nanoparticles. These molecules sequester nucleic acids for delivery to cells. However, to build more efficacious delivery molecules, the field must continue to broaden structure-function studies for greater insight. While nucleic acid-binding efficiency, degradability and nanoparticle stability are vitally important, this review offers perspective on additional factors that must be addressed to improve delivery efficiencyAreas coveredWe discuss how administration route, cellular heterogeneity, uptake pathway, endosomal escape timing, age, sex, and threshold effects can change depending on the type of LNP ionizable *** opinionIonizable lipid structure-function studies often focus on the efficiency of RNA utilization and biodistribution. While these focus areas are critical, they remain high-level observations. As our tools for observation and system interrogation improve, we believe that the field should begin collecting additional data. At the cellular level, this data should include age (dividing or senescent cells), sex and phenotype, cell entry pathway, and endosome type. Additionally, administration route and dose are essential to track. This additional data will allow us to identify and understand heterogeneity in LNP efficacy across patient populations, which will help us provide better ionizable lipid options for different groups.

关键词： Ionizable lipid ribonucleic acid RNA lipid nanoparticle LNP functional delivery uptake mechanism endosomal escape structure-function patient stratification

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Clues to reaction specificity in PLP-dependent fold type I aminotransferases of monosaccharide biosynthesis

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PROTEINS-structure function AND BIOINFORMATICS 2022年第6期90卷 1247-1258页

作者： Srivastava, Jaya Balaji, Petety V. Indian Inst Technol Dept Biosci & Bioengn Mumbai Maharashtra India

Novel functions can emerge in an enzyme family while conserving catalytic mechanism, motif or fold. Pyridoxal 5'-phosphate-dependent enzymes have evolved into seven fold-types and catalyze diverse reactions using the same mechanism for the formation of external aldimine. Nucleotide sugar aminotransferases (which will be henceforth referred to as aminotransferases) belong to fold type I and mediate the biosynthesis of several monosaccharides. They use diverse substrates but are highly selective to the C3 or C4 carbon to which amine group is transferred. Profile hidden Markov models (HMMs) were able to identify aminotransferases but could not capture reaction specificity. A search for discriminating features led to the discovery of sequence motifs that are located near the pyranose binding site suggesting their role in imparting reaction specificity. Using a position weight matrix for this motif, we were able to assign reaction specificity to a large number of aminotransferases. Inferences from this analysis set way for future experiments that can shed light on mechanisms of functional diversification in nucleotide sugar aminotransferases of fold type I.

关键词： bioinformatics motifs profile HMMs structure-function sugar aminotransferases

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Structural control of fibrin bioactivity by mechanical deformation

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2022年第22期119卷 e2117675119-e2117675119页

作者： Kumar, Sachin Wang, Yujen Hedayati, Mohammadhasan Fleissner, Frederik Rausch, Manuel K. Parekh, Sapun H. Univ Texas Austin Dept Biomed Engn Austin TX 78712 USA Indian Inst Technol Delhi Ctr Biomed Engn Hauz Khas New Delhi 110016 India All India Inst Med Sci Dept Biomed Engn New Delhi 110029 India Max Planck Inst Polymer Res Mol Spect Dept D-55128 Mainz Germany Univ Texas Austin Oden Inst Computat Engn & Sci Austin TX 78712 USA Univ Texas Austin Dept Aerosp Engn & Engn Mech Austin TX 78712 USA

Fibrin is the fibrous protein network that comprises blood clots;it is uniquely capable of bearing very large tensile strains (up to 200%) due to multiscale force accommodation mechanisms. Fibrin is also a biochemical scaffold for numerous enzymes and blood factors. The biomechanics and biochemistry of fibrin have been independently studied. However, comparatively little is known about how fibrin biomechanics and biochemistry are coupled: how does fibrin deformation influence its biochemistry? In this study, we show that mechanically induced protein structural changes in fibrin affect fibrin biochemistry. We find that tensile deformation of fibrin leads to molecular structural transitions of a-helices to beta-sheets, which reduced binding of tissue plasminogen activator (tPA), an enzyme that initiates fibrin lysis. Moreover, binding of tPA and Thioflavin T, a commonly used beta-sheet marker, were mutually exclusive, further demonstrating the mechano-chemical control of fibrin biochemistry. Finally, we demonstrate that structural changes in fibrin suppressed the biological activity of platelets on mechanically strained fibrin due to reduced aIIb beta 3 integrin binding. Our work shows that mechanical strain regulates fibrin molecular structure and biological activity in an elegant mechanochemical feedback loop, which possibly extends to other fibrous biopolymers.

关键词： fibrin structure-function mechanochemistry extracellular matrix

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Associations between steady-state pattern electroretinography and estimated retinal ganglion cell count in glaucoma suspects

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DOCUMENTA OPHTHALMOLOGICA 2022年第1期145卷 11-25页

作者： Tirsi, Andrew Orshan, Derek Wong, Benny Gliagias, Vasiliki Tsai, Joby Obstbaum, Stephen A. Tello, Celso Northwell Hlth Dept Ophthalmol Manhattan Eye Ear & Throat Hosp New York NY 10065 USA Donald & Barbara Zucker Sch Med Hofstra Northwell Hempstead NY USA Diopsys Inc New York NJ USA New York Inst Technol Coll Osteopath Med Glen Head NY USA

Purpose To estimate retinal ganglion cell (RGC) count in glaucoma suspects (GS) and ascertain its relationships with steady-state pattern electroretinography (ssPERG) parameters. Methods In this prospective cross-sectional study, 22 subjects (44 eyes) were recruited at the Manhattan Eye, Ear, and Throat Hospital. Subjects underwent complete eye examinations, optical coherence tomography, standard automated perimetry, and ssPERG testing. Eyes were divided into two groups based upon clinical data: healthy subjects and GS. RGC count was estimated using the combined structure-function index. Results Estimated RGC count, average retinal nerve fiber layer thickness (ARNFLT), and average ganglion cell layer and inner plexiform layer thickness (GCIPLT) were reduced in GS eyes (p <= 0.001 for all parameters). Pearson correlations revealed that ssPERG magnitude and magnitudeD correlated with ARNFLT (r >= 0.53, p < 0.001), GCIPLT (r > 0.38, p < 0.011), and estimated RGC count (r > 0.46, p < 0.002). Six mediation analyses revealed that estimated RGC count mediated the relationships among ssPERG parameters, ARNFLT, and GCIPLT. Conclusion Steady-state PERG parameters demonstrated linear correlations with estimated RGC count. The associations among ssPERG parameters and structural measures were mediated by estimated RGC count.

关键词： CSFI PERG Glaucoma Mediation structure-function

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