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Isotopic Labeling-Enabled Chemical Proteomics Analysis Revealed structural and Functional Features of Allysine Modifications in Mammalian Cells and Tissues

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Analytical Chemistry 2025年第18期97卷 9944-9952页

作者： Sin, Yi-Cheng Hosny, Nora Batti Angulski, Addeli Bez Kim, Do-Hyung Metzger, Joseph M. Chen, Yue Department of Biochemistry Molecular Biology and Biophysics University of Minnesota at Twin Cities MinneapolisMN55455 United States Department of Integrative Biology and Physiology University of Minnesota at Twin Cities MinneapolisMN55455 United States Bioinformatics and Computational Biology Program University of Minnesota at Twin Cities MinneapolisMN55455 United States

Allysine is a pivotal protein post-translational modification that regulates protein interaction and activities. It is also recognized as a marker of oxidative stress under certain metabolic and physiological conditions. In this study, we developed a capture-and-release chemical proteomics workflow with heavy isotopic labeling that enables system-wide enrichment and site-specific identification of allysine as well as other carbonylated peptides, such as peptides containing glutamic semialdehyde derived from the oxidative damage of arginine and proline, with high confidence. The streamlined workflow led to the identification of 434 allysine sites on 349 proteins in human 293T and HCT116 cells and 317 allysine sites on 157 proteins in mouse muscle tissues without any treatment with an oxidative stress-inducing chemical reagent. We identified 48 histone allysine sites, including 38 sites on core histones in human 293T cells, many of which overlapped with well-characterized histone acetylation and methylation epigenetic marks. Bioinformatic analysis revealed notable characteristics of the amino acid preferences of allysine flanking sequences and the significant depletion of allysine sites in the protein secondary structure in cultured human cells. Pathway analysis showed that allysine substrates were involved in diverse cellular processes including translation, protein folding, and RNA processing in human cells and were enriched with muscle contractile fiber proteins and metabolic enzymes in mouse muscle tissue. Thus, our integrated chemical proteomics analysis revealed the structural and functional features of allysine targets under regular growth conditions in cultured human cells and mouse tissues. © 2025 American Chemical Society.

关键词： Proteolysis

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The pentameric chloride channel BEST1 is activated by extracellular GABA

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Proceedings of the National Academy of Sciences of the United States of America 2025年第16期122卷 e2424474122页

作者： Pant, Swati Tam, Stephanie W. Long, Stephen B. Structural Biology Program Memorial Sloan Kettering Cancer Center New York 10065 NY United States Graduate Program in Biochemistry and Structural Biology Cell and Developmental Biology and Molecular Biology Weill Cornell Medicine Graduate School of Medical Sciences New York 10065 NY United States Graduate Program in Physiology Biophysics and Systems Biology Weill Cornell Medicine Graduate School of Medical Sciences New York 10065 NY United States

Bestrophin-1 (BEST1) is a chloride channel expressed in the eye and other tissues of the body. A link between BEST1 and the principal inhibitory neurotransmitter γ-aminobutyric acid (GABA) has been proposed. The most appreciated receptors for extracellular GABA are the GABA_B G-protein-coupled receptors and the pentameric GABA_A chloride channels, both of which have fundamental roles in the central nervous system. Here, we demonstrate that BEST1 is directly activated by GABA. Through functional studies and atomic-resolution structures of human and chicken BEST1, we identify a GABA binding site on the channel’s extracellular side and determine the mechanism by which GABA binding stabilizes opening of the channel’s central gate. This same gate, “the neck,” is activated by intracellular [Ca²⁺], indicating that BEST1 is controlled by ligands from both sides of the membrane. The studies demonstrate that BEST1, which shares no structural homology with GABA_A receptors, is a GABA-activated chloride channel. The physiological implications of this finding remain to be studied. © 2025 the Author(s).

关键词： activation bestrophin chloride channel GABA receptor

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Activity and structure of human (d)CTP deaminase CDADC1

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Proceedings of the National Academy of Sciences of the United States of America 2025年第19期122卷 e2424245122页

作者： Slyvka, Anton Rathore, Ishan Yang, Renbin Gewartowska, Olga Kanai, Tapan Lountos, George T. Skowronek, Krzysztof Czarnocki-Cieciura, Mariusz Wlodawer, Alexander Bochtler, Matthias Laboratory of Structural Biology International Institute of Molecular and Cell Biology in Warsaw Warsaw 02-109 Poland Center for Structural Biology National Cancer Institute NIH Frederick MD 21702 United States Cancer Research Technology Program Leidos Biomedical Research Inc. Frederick United States Genome Engineering Facility International Institute of Molecular and Cell Biology in Warsaw Warsaw 02-109 Poland Basic Science Program Frederick National Laboratory for Cancer Research Frederick MD 21702 United States Biophysics Facility International Institute of Molecular and Cell Biology in Warsaw Warsaw 02-109 Poland Laboratory of Protein Structure International Institute of Molecular and Cell Biology in Warsaw Warsaw 02-109 Poland Institute of Biochemistry and Biophysics Warsaw 02-106 Poland

Vertebrates have evolved an understudied protein termed CDADC1 (NYD-SP15) that contains an inactive N-terminal and active C-terminal DCTD-like domain. Here, we show that human CDADC1 is a (d)CTP-specific deaminase, with a roughly 2-fold in vitro preference for dCTP over CTP. We determined high-resolution cryo-EM structures of CDADC1 in the absence of substrate and in complex with dCTP and 5-methyl-dCTP. The structures show that CDADC1 forms trimers and dimers of trimers in solution. The (d)CTP substrate is selected by a narrow pocket for the cytosine base and multiple lysine and arginine contacts to the triphosphate. Substrate binding promotes the association of trimers into hexamers and the transition of the hexamers from a loose to a tighter arrangement. Genetic experiments in mice show that loss of Cdadc1 is surprisingly well tolerated, even in the absence of the dCMP deaminase Dctd that is considered as the main source of dUMP, the precursor of dTTP. Copyright © 2025 the Author(s).

关键词： cryoelectron microscopy cytidine deaminase nucleotide metabolism triphosphate

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Elucidation and Prevention of an Unexpected Methylamine Byproduct Formed During Trifluoroacetic Acid-Mediated Side Chain Deprotection of Azido-Containing Peptides

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International Journal of Peptide Research and Therapeutics 2025年第4期31卷 1-12页

作者： Xie, Yixin Lopez-Silva, Tania L. Dyba, Marzena A. Grkovic, Tanja Schneider, Joel P. Chemical Biology Laboratory Center for Cancer Research National Cancer Institute National Institutes of Health Frederick 21702 MD United States Biophysics Resource Center for Structural Biology Center for Cancer Research National Cancer Institute National Institutes of Health Frederick 21702 MD United States Molecular Targets Program Center for Cancer Research National Cancer Institute National Institutes of Health Frederick 21702 MD United States Natural Products Branch Developmental Therapeutics Program Division of Cancer Treatment and Diagnosis National Cancer Institute National Institutes of Health Frederick 21702 MD United States

Purpose: We found that a byproduct characterized by a difference of 12 mass units is formed during TFA-mediated cleavage of azide-containing peptides from solid support. This study identifies this byproduct, provides a rationale for its formation and a solution for its inhibition. Method: NMR and HRMS analyses as well as chemical synthesis is employed to identify the byproduct and probe the mechanism of its formation. Results: Data is consistent with the conversion of azide to methylamine which occurs during peptide cleavage likely via a Schmidt rearrangement involving nucleophilic azide attack of t-butyl cations generated from the side chain deprotection of Boc- and t-butyl ether groups. Conclusion: Installing azide-containing residues using the newly reported 2-(trimethylsilyl)ethoxycarbonyl (Teoc)-protected compound 3a proved effective at significantly thwarting the formation of methylamine byproduct. © This is a U.S. Government work and not under copyright protection in the US;foreign copyright protection may apply 2025.

关键词： Azide Azido lysine Byproduct Click Ligation Peptide

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Quantum variational autoencoder utilizing regularized mixed-state latent representations

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Physical Review A 2025年第4期111卷 042416-042416页

作者： Gaoyuan Wang Jonathan Warrell Prashant S. Emani Mark Gerstein Program in Computational Biology and Bioinformatics Yale University New Haven Connecticut 06520 USA Department of Molecular Biophysics and Biochemistry Yale University New Haven Connecticut 06520 USA NEC Laboratories America Princeton New Jersey 08540 USA Department of Computer Science Yale University New Haven Connecticut 06520 USA Department of Statistics & Data Science Yale University New Haven Connecticut 06520 USA Department of Biomedical Informatics & Data Science Yale University New Haven Connecticut 06520 USA

A major challenge in near-term quantum computing is its application to large real-world datasets due to scarce quantum hardware resources. One approach to enabling tractable quantum models for such datasets involves finding low-dimensional representations that preserve essential information for downstream analysis. In classical machine learning, variational autoencoders (VAEs) facilitate efficient data compression, representation learning for subsequent tasks, and novel data generation. However, no quantum model has been proposed that exactly captures all of these features for direct application to quantum data on quantum computers. Some existing quantum models for data compression lack regularization of latent representations, thus preventing direct use for generation and control of generalization. Others are hybrid models with only some internal quantum components, impeding direct training on quantum data. To address this, we present a fully quantum framework, ζ-QVAE, which encompasses all the capabilities of classical VAEs and can be directly applied to map both classical and quantum data to a lower-dimensional space, while effectively reconstructing much of the original state from it. Our model utilizes regularized mixed states to attain optimal latent representations. It accommodates various divergences for reconstruction and regularization. Furthermore, by accommodating mixed states at every stage, it can utilize the full data density matrix and allow for a training objective defined on probabilistic mixtures of input data. Doing so, in turn, makes efficient optimization possible and has potential implications for private and federated learning. In addition to exploring the theoretical properties of ζ-QVAE, we demonstrate its performance on representative genomics and synthetic data. Our results indicate that ζ-QVAE consistently learns representations that better utilize the capacity of the latent space and exhibits similar or better performance compared with

关键词： Quantum computers

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The condensin holocomplex cycles dynamically between open and collapsed states (Sep, 10.1038/s41594-020-0508-3, 2020)

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NATURE structural & molecular biology 2020年第12期27卷 1211-1211页

作者： Ryu, Je-Kyung Katan, Allard J. van der Sluis, Eli O. Wisse, Thomas de Groot, Ralph Haering, Christian H. Dekker, Cees Department of Bionanoscience Kavli Institute of Nanoscience Delft Delft University of Technology Delft the Netherlands Cell Biology and Biophysics Unit Structural and Computational Unit European Molecular Biology Laboratory (EMBL) Heidelberg Germany

structural maintenance of chromosome (SMC) protein complexes are the key organizers of the spatiotemporal structure of chromosomes. The condensin SMC complex has recently been shown to be a molecular motor that extrudes large loops of DNA, but the mechanism of this unique motor remains elusive. Using atomic force microscopy, we show that budding yeast condensin exhibits mainly open ‘O’ shapes and collapsed ‘B’ shapes, and it cycles dynamically between these two states over time, with ATP binding inducing the O to B transition. Condensin binds DNA via its globular domain and also via the hinge domain. We observe a single condensin complex at the stem of extruded DNA loops, where the neck size of the DNA loop correlates with the width of the condensin complex. The results are indicative of a type of scrunching model in which condensin extrudes DNA by a cyclic switching of its conformation between O and B shapes.

关键词： Atomic force microscopy Nuclear organization Single-molecule biophysics

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New site-specific protein functionality with a click

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BioSpektrum 2016年第7期22卷 704-707页

作者： Koehler, Christine Lemke, Edward A. European Molecular Biology Laboratory (EMBL) Structural and Computational Biology Unit Cell Biology and Biophysics Unit Meyerhofstraße 1 Heidelberg D-69117 Germany

Genetic encoding of custom designed non-canonical amino acids has emerged as one of the most versatile tools to install site-specific “click-reactive” functionalities into proteins. These non-toxic groups can readily react with suitable substances carrying a compatible clickchemistry. The technology can be used for a variety of applications, such as fluorescent labelling of protein in cells to visualize molecular machines and to custom-engineer better drugs. © 2016, Springer-Verlag Berlin Heidelberg.

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BPS2025 - Sticker strength modulates intrachain vs. interchain tug-of-war in multivalent disordered regions

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Biophysical Journal 2025年第3期124卷 557a-557a页

作者： David Moses Garrett M. Ginell Alex S. Holehouse Shahar Sukenik Department of Integrative Structural and Computational Biology Scripps Research La Jolla CA USA Department of Biochemistry and Molecular Biophysics Washington University in St. Louis St. Louis MO USA Department of Chemistry Syracuse University Syracuse NY USA

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A Designed Zn²⁺ Sensor Domain Transmits Binding Information to Transmembrane Histidine Kinases

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Journal of the American Chemical Society 2025年 2025 May 19页

作者： Hatstat, A. Katherine Kormos, Rian Xu, Vee Du, Guoming Liu, Lijun Zhang, Shao-Qing DeGrado, William F. Department of Pharmaceutical Chemistry University of California San Francisco 94158-9001 CA United States The Cardiovascular Research Institute University of California at San Francisco San Francisco 94158-9001 CA United States Biophysics Graduate Program University of California San Francisco 94158-9001 CA United States Biotechnology Program City College of San Francisco San Francisco 94112 CA United States Shanghai Institute of Biochemistry and Cell Biology Center for Excellence in Molecular Cell Science Chinese Academy of Sciences Shanghai 200031 China Protein Structure and X-ray Crystallography Laboratory Structural Biology Center University of Kansas Lawrence 66047 KS United States

Generating stimulus-responsive allosteric signaling de novo is a significant challenge in protein design. In natural systems like bacterial histidine kinases (HKs), signal transduction occurs when ligand binding initiates a signal that is amplified across biological membranes over long distances to induce large-scale rearrangements and phosphorylation relays. Here, we ask whether our understanding of protein design and multidomain, intramolecular signaling has progressed sufficiently to enable engineering of a HK with tunable de novo components. We generated de novo metal-binding sensor domains and substituted them for the native sensor domain of a transmembrane HK, affording chimeras that transduce signals initiated from a de novo sensor. Signaling depended on the designed sensor’s stability and the interdomain linker’s phase and length. These results show the usefulness of de novo design to elucidate the biochemical mechanisms and principles of transmembrane signaling. © 2025 American Chemical Society.

关键词： Signaling

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A multi-omic approach implicates novel protein dysregulation in post-traumatic stress disorder

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Genome Medicine 2025年第1期17卷 1-19页

作者： Wang, Jiawei Liu, Yujing Li, Hongyu Nguyen, Tuan P. Soto-Vargas, John Lee Wilson, Rashaun Wang, Weiwei Lam, TuKiet T. Zhang, Chi Lin, Chen Wolf, Erika J. Williamson, Douglas E. Ursano, Robert Stein, Thor DiSano, Krista Schnurr, Paula Scott, William K. Pierce, Meghan Montalvo-Ortiz, Janitza Noller, Crystal Miller, Mark W. Marx, Brian McKee, Ann Logue, Mark W. Keane, Terence M. Labadorf, Adam T. Kaye, Alfred Huber, Bertrand R. Hoffman, Ellen Davis, David A. Cruz, Dianne A. Che, Alicia Benedek, David Alvarez, Victor E. Lewis, David A. Glausier, Jill Holtzheimer, Paul E. Friedman, Matthew J. Williams, Kenneth R. Picciotto, Marina R. Nairn, Angus C. Krystal, John H. Duman, Ronald S. Young, Keith A. Zhao, Hongyu Girgenti, Matthew J. Program of Computational Biology & Bioinformatics Yale University New Haven 06511 CT United States Department of Psychiatry Yale School of Medicine New Haven 06511 CT United States Department of Biostatistics Yale School of Public Health New Haven 06510 CT United States NIDA Neuroproteomics Center Yale School of Medicine New Haven 06511 CT United States Department of Molecular Biophysics and Biochemistry Yale School of Medicine New Haven 06511 CT United States Keck MS & Proteomics Resource Yale School of Medicine New Haven 06510 CT United States Department of Psychiatry University of Pittsburgh Pittsburgh 15213 PA United States Department of Psychiatry Geisel School of Medicine at Dartmouth Lebanon 03756 NH United States Central Texas Veterans Health Care System Research Service Temple 76504 TX United States Department of Psychiatry and Behavioral Sciences Texas A & M University School of Medicine Bryan 77807 TX United States National Center for PTSD United States Department of Veterans Affairs White River Junction 05009 VT United States

Background : Post-traumatic stress disorder (PTSD) is a common and disabling psychiatric disorder. PTSD involves multiple brain regions and is often comorbid with other psychiatric disorders, such as major depressive disorder (MDD). Recent genome-wide association studies (GWASs) have identified many PTSD risk loci and transcriptomics studies of postmortem brain have found differentially expressed genes associated with PTSD cases. In this study, we integrated genome-wide measures across modalities to identify convergent molecular effects in the PTSD brain. Methods: We performed tandem mass spectrometry (MS/MS) on a large cohort of donors (N = 66) in two prefrontal cortical areas, dorsolateral prefrontal cortex (DLPFC), and subgenual prefrontal cortex (sgPFC). We also coupled the proteomics data with transcriptomics and microRNA (miRNA) profiling from RNA-seq and small-RNA sequencing, respectively for the same cohort. Additionally, we utilized published GWAS results of multiple psychiatric disorders for integrative analysis. Results: We found differentially expressed proteins and co-expression protein modules disrupted by PTSD. Integrative analysis with transcriptomics and miRNA data from the same cohort pointed to hsa-mir-589 as a regulatory miRNA responsible for dysregulation of neuronal protein networks for PTSD, including the gamma-aminobutyric acid (GABA) vesicular transporter, SLC32A1. In addition, we identified significant enrichment of risk genes for other psychiatric disorders, such as autism spectrum disorder (ASD) and major depressive disorder (MDD) within PTSD protein co-expression modules, suggesting shared molecular pathology. Conclusions: We integrated genome-wide measures of mRNA and miRNA expression and proteomics profiling from PTSD, MDD, and control (CON) brains to identify convergent and divergent molecular processes across genomic modalities. We substantially expand the number of differentially expressed genes and proteins in PTSD and identify dow

关键词： Major depressive disorder MicroRNAs Multi-omics Prefrontal cortex PTSD

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