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Variations in kinase and effector signaling logic in a bacterial two component signaling network

Journal of Biological Chemistry 2025年第6期301卷 108534页

作者： Swingle, Danielle Epstein, Leah Aymon, Ramisha Isiorho, Eta A. Abzalimov, Rinat R. Favaro, Denize C. Gardner, Kevin H. Structural Biology Initiative CUNY Advanced Science Research Center New YorkNY United States PhD. Program in Biochemistry The Graduate Center – City University of New York New YorkNY United States Department of Chemistry and Biochemistry City College of New York New YorkNY United States PhD. Programs in Biochemistry Biology and Chemistry The Graduate Center – City University of New York New YorkNY United States

The general stress response (GSR) protects bacteria from a wide range of stressors. In Alphaproteobacteria, GSR activation is coordinated by HWE/HisKA2 family histidine kinases (HKs), which can exhibit noncanonical structure and function. For example, while most light-oxygen-voltage sensor-containing HKs are light-activated dimers, the Rubellimicrobium thermophilum RT-HK has inverted "dark on, light off" signaling logic with a tunable monomer/dimer equilibrium. Here, we further investigate these atypical behaviors of RT-HK and characterize its downstream signaling network. Using hydrogen-deuterium exchange mass spectrometry, we find that RT-HK uses a signal transduction mechanism similar to light-activated systems, despite its inverted logic. Mutagenesis reveals that RT-HK autophosphorylates in trans, with changes to the Jα helix linking sensor and kinase domains affecting autophosphorylation levels. Exploring downstream effects of RT-HK, we identified two GSR genetic regions, each encoding a copy of the central regulator PhyR. In vitro measurements of phosphotransfer from RT-HK to the two putative PhyRs revealed that RT-HK signals only to one and does so at an increased intensity in the dark, consistent with its reversed logic. X-ray crystal structures of both PhyRs revealed a substantial shift within the receiver domain of one, suggesting a basis for RT-HK specificity. We probed further down the pathway using nuclear magnetic resonance to determine that the single NepR homolog interacts with both unphosphorylated PhyRs, and this interaction is decoupled from activation in one PhyR. This work expands our understanding of HWE/HisKA2 family signal transduction, revealing marked variations from signaling mechanisms previously identified in other GSR networks. © 2025 The Authors

关键词： Signaling

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Chaperone proteins as ameliorators of α-synuclein-induced synaptic pathologies: insights into Parkinson’s disease

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Neural Regeneration Research 2021年第6期16卷 1198-1199页

作者： Susan M.L.Banks Audrey T.Medeiros Rui Sousa Eileen M.Lafer Jennifer R.Morgan Department of Biology Florida Southern CollegeLakelandFLUSA Neuroscience Graduate Program Brown UniversityProvidenceRIUSA Department of Biochemistry and Structural Biology and Center for Biomedical Neuroscience The University of Texas Health Science Center at San AntonioSan AntonioTXUSA The Eugene Bell Center for Regenerative Biology&Tissue Engineering Marine Biological LaboratoryWoods HoleMAUSA

α-Synuclein accumulation causes synaptic vesicle trafficking defects and may underlie neurodegenerative disorders:Neurodegenerative disorders,such as Parkinson’s disease(PD)and other synucleinopathies,impact the lives of millions of patients and their *** include PD,dementia with Lewy Bodies(DLB),multiple system atrophy,and several Alzheimer’s Disease *** are clinically characterized by intracellular inclusions called Lewy Bodies,which are rich in atypical aggregates of the protein α-*** dopaminergic neurons in the substantia nigra are particularly susceptible toα-synuclein-induced aggregation and neurodegeneration,glutamatergic neurons in other brain regions(***)are also frequently affected in PD and other synucleinopathies(Schulz-Schaeffer 2010).

关键词： cortex Alzheimer insight

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structural insights into TDP-43 in nucleic-acid binding and domain interactions

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Nucleic Acids Research 2009年第6期37卷 1799-1808页

作者： Kuo, Pan-Hsien Doudeva, Lyudmila G. Wang, Yi-Ting Shen, Che-Kun James Yuan, Hanna S. Institute of Bioinformatics and Structural Biology National Tsing Hua University Taipei Taiwan Institute of Molecular Biology National Taiwan University Taipei Taiwan Taiwan International Graduate Program Chemical Biology and Molecular Biophysics National Taiwan University Taipei Taiwan Graduate Institute of Biochemistry and Molecular Biology National Taiwan University Taipei Taiwan

TDP-43 is a pathogenic protein: its normal function in binding to UG-rich RNA is related to cystic fibrosis, and inclusion of its C-terminal fragments in brain cells is directly linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here we report the 1.65 Å crystal structure of the C-terminal RRM2 domain of TDP-43 in complex with a single-stranded DNA. We show that TDP-43 is a dimeric protein with two RRM domains, both involved in DNA and RNA binding. The crystal structure reveals the basis of TDP-43's TG/ UG preference in nucleic acids binding. It also reveals that RRM2 domain has an atypical RRM-fold with an additional β-strand involved in making protein-protein interactions. This self association of RRM2 domains produced thermal-stable RRM2 assemblies with a melting point greater than 85°C as monitored by circular dichroism at physiological conditions. These studies thus characterize the recognition between TDP-43 and nucleic acids and the mode of RRM2 self association, and provide molecular models for understanding the role of TDP-43 in cystic fibrosis and the neurodegenerative diseases related to TDP-43 proteinopathy. © 2009 The Author(s).

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Redesign of high-affinity nonspecific nucleases with altered sequence preference

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Journal of the American Chemical Society 2009年第47期131卷 17345-17353页

作者： Wang, Yi-Ting Wright, Jon D. Doudeva, Lyudmila G. Jhang, Hua-Ci Lim, Carmay Yuan, Hanna S. Institute of Molecular Biology Academia Sinica Taipei Taiwan Institute of Biomedical Sciences Academia Sinica Taipei Taiwan Institute of Chemical Biology and Molecular Biophysics Taiwan International Graduate Program Academia Sinica Taipei Taiwan Institute of Bioinformatics and Structural Biology Department of Chemistry National Tsing Hua University HsinChu Taiwan Institute of Biochemistry and Molecular Biology National Taiwan University Taipei Taiwan

It is of crucial importance to elucidate the underlying principles that govern the binding affinity and selectivity between proteins and DNA. Here we use the nuclease domain of Colicin E7 (nColE7) as a model system to generate redesigned nucleases with improved DNA-binding affinities. ColE7 is a bacterial toxin, bearing a nonspecific endonuclease domain with a preference for hydrolyzing DNA phosphodiester bonds at the 3O-side after thymine and adenine;i.e., it prefers Thy and Ade at the -1 site. Using systematic computational screening, six nColE7 mutants were predicted to bind DNA with high affinity. Five of the redesigned single-point mutants were constructed and purified, and four mutants had a 3- to 5-fold higher DNA binding affinity than wild-type nColE7 as measured by fluorescence kinetic assays. Moreover, three of the designed mutants, D493N, D493Q, and D493R, digested DNA with an increased preference for guanine at +3 sites compared to the wild-type enzyme, as shown by DNA footprint assays. X-ray structure determination of the ColE7 mutant D493Q-DNA complex in conjunction with structural and free energy decomposition analyses provides a physical basis for the improved protein-DNA interactions: Replacing D493 at the protein-DNA interface with an amino acid residue that can maintain the native hydrogen bonds removes the unfavorable electrostatic repulsion between the negatively charged carboxylate and DNA phosphate groups. These results show that computational screening combined with biochemical, structural, and free energy analyses provide a useful means for generating redesigned nucleases with a higher DNA-binding affinity and altered sequence preferences in DNA cleavage. © 2009 American Chemical Society.

关键词： DNA

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Mapping the interaction surface between Ca_Vβ and actin and its role in calcium channel clearance

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Nature Communications 2025年第1期16卷 1-21页

作者： Castilla, Francisco Lugo, Victor Miranda-Laferte, Erick Jordan, Nadine Huesgen, Pitter F. Santiago-Schübel, Beatrix Alfonso-Prieto, Mercedes Hidalgo, Patricia Institute of Biological Information Processing (IBI-1)—Molecular and Cellular Physiology Forschungszentrum Jülich Jülich Germany Graduate Program Faculty of Mathematics and Natural Sciences Heinrich-Heine University Düsseldorf Germany Central Institute of Engineering Electronics and Analytics (ZEA-3) Forschungszentrum Jülich Jülich Germany Institute of Biological Information Processing (IBI-7)—Structural Biochemistry Forschungszentrum Jülich Jülich Germany Institute of Neuroscience and Medicine (INM-9)—Computational Biomedicine Forschungszentrum Jülich Jülich Germany Cécile and Vogt Institute for Brain Research Medical Faculty Heinrich-Heine University Düsseldorf Germany Institute of Biochemistry Heinrich-Heine University Düsseldorf Germany Biologics Analytical Research and Development AbbVie Deutschland GmbH & Co. KG Ludwigshafen Germany Institute of Biology II University of Freiburg Freiburg Germany

Defective ion channel turnover and clearance of damaged proteins are associated with aging and neurodegeneration. The L-type CaV1.2 voltage-gated calcium channel mediates depolarization-induced calcium signals in hear...

Defective ion channel turnover and clearance of damaged proteins are associated with aging and neurodegeneration. The L-type Ca_V1.2 voltage-gated calcium channel mediates depolarization-induced calcium signals in heart and brain. Here, we determined the interaction surface between actin and two calcium channel subunits, Ca_Vβ₂ and Ca_Vβ₄, using cross-linking mass spectrometry and protein-protein docking, and uncovered a role in replenishing conduction-defective Ca_V1.2 channels. Computational and in vitro mutagenesis identified hotspots in Ca_Vβ that decreased the affinity for actin but not for Ca_V1.2. When coexpressed with Ca_V1.2, none of the tested actin-association-deficient Ca_Vβ mutants altered the single-channel properties or the total number of channels at the cell surface. However, coexpression with the Ca_Vβ₂ hotspot mutant downregulated current amplitudes, and with a concomitant reduction in the number of functionally available channels, indicating that current inhibition resulted from a build-up of conduction silent channels. Our findings established Ca_Vβ₂–actin interaction as a key player for clearing the plasma membrane of corrupted Ca_V1.2 proteins to ensure the maintenance of a functional pool of channels and proper calcium signal transduction. The Ca_Vβ–actin molecular model introduces a potentially druggable protein-protein interface to intervene Ca_V-mediated signaling processes. © The Author(s) 2025.

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Amyloid formation in heterogenous environments:Glycosoaminoglycans can induce amyloid formation by non-amyloidogenic proteins and interfere with amyloid inhibitors

Amyloid formation in heterogenous environments:Glycosoaminog...

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The 3rd Asia Pacific Protein Association Conference in Conjunction with the 3rd Symposium of the Chinese Protein Society

作者： Hui Wang Fanling Meng Daniel P.Raleigh Department of Chemistry State University of New York at Stony Brook Graduate Program in Biochemistry and Structural Biology Graduate Program in BiophysicsState University of New York at Stony Brook

Amyloid formation,the aggregation of normally soluble proteins into partially orderedβ-rich structures,is a characteristic component of many human *** formation takes place in a heterogenous environment in vivo with the potential for interactions with membranes and with components of the extracellular matrix.A range of strategies have been applied to the problem of developing inhibitors of amyloid formation,however,the majority of in vitro assays of amyloid formation and amyloid

关键词： Amyloid formation in heterogenous environments:Glycosoaminoglycans can induce amyloid formation by non-amyloidogenic proteins and interfere with amyloid inhibitors

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Going Deeper in Cryo Electron Tomography with Neural Networks

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Microscopy and Microanalysis 2017年第S1期23卷 814-815页

作者： Muyuan Chen Wei Dai Stella Y. Sun Michael F. Schmid Wah Chiu Steven J. Ludtke Graduate Program in Structural and Computational Biology and Molecular Biophysics Baylor College of Medicine Houston TX Verna Marrs and McLean Department of Biochemistry and Molecular Biology Baylor College of Medicine Houston TX

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Graph-based information diffusion method for prioritizing functionally related genes in protein-protein interaction networks 25

Graph-based information diffusion method for prioritizing fu...

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25th Pacific Symposium on Biocomputing, PSB 2020

作者： Pham, Minh Lichtarge, Olivier Integrative Molecular and Biomedical Sciences Graduate Program Department of Molecular and Human Genetics Baylor College of Medicine One Baylor Plaza HoustonTX77030 United States Departments of Molecular and Human Genetics Structural and Computational Biology and Molecular Biophysics Biochemistry and Molecular Biology and Pharmacology One Baylor Plaza HoustonTX77030 United States

Shortest path length methods are routinely used to validate whether genes of interest are functionally related to each other based on biological network information. However, the methods are computationally intensive, impeding extensive utilization of network information. In addition, nonweighted shortest path length approach, which is more frequently used, often treat all network connections equally without taking into account of confidence levels of the associations. On the other hand, graph-based information diffusion method, which employs both the presence and confidence weights of network edges, can efficiently explore large networks and has previously detected meaningful biological patterns. Therefore, in this study, we hypothesized that the graph-based information diffusion method could prioritize genes with relevant functions more efficiently and accurately than the shortest path length approaches. We demonstrated that the graph-based information diffusion method substantially differentiated not only genes participating in same biological pathways (p 0.0001) but also genes associated with specific human drug-induced clinical symptoms (p 0.0001) from random. Furthermore, the diffusion method prioritized these functionally related genes faster and more accurately than the shortest path length approaches (pathways: p = 2.7e-28, clinical symptoms: p = 0.032). These data show the graph-based information diffusion method can be routinely used for robust prioritization of functionally related genes, facilitating efficient network validation and hypothesis generation, especially for human phenotypespecific genes. © 2019 The Authors.

关键词： Genes

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structural insights into TDP-43, a new player in neurodegenerative diseases

Structural insights into TDP-43, a new player in neurodegene...

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亚洲晶体学联合大会

作者： Pan-Hsien Kuo Lyudmila G.Doudeva Che-Kun James Shen Hanna S.Yuan Institute of Bioinformatics and Structural Biology National Tsing Hua University Institute of Molecular Biology Academia Sinica Taiwan International Graduate Program Chemical Biology and Molecular BiophysicsAcademia Sinica Graduate Institute of Biochemistry and Molecular Biology National Taiwan University

关键词： TDP RNA domain structural insights into TDP-43 a new player in neurodegenerative diseases

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Seeing the Portal in Membrane-containing Bacteriophage PRD1 by Cryo-EM

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Microscopy and Microanalysis 2014年第S3期20卷 1250-1251页

作者： Chuan Hong Xiangan Liu Hanna M. Oksanen Joanita Jakana Dennis H. Bamford Wah Chiu Graduate Program in Structural and Computational Biology and Molecular Biophysics Department of Biochemistry and Molecular Biology Baylor College of Medicine Houston TX 77030 USA Institute of Biotechnology and Department of Biosciences University of Helsinki FIN-00014 Helsinki Finland

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