Article
Biology
Jingliang Zhang, Chenyu Zhang, Xiaoling Chen, Bingwei Wang, Weining Ma, Yang Yang, Ruimao Zheng, Zhuo Huang
Summary: Temporal lobe epilepsy (TLE) is a common and intractable neurological disorder, with dysfunctional PKA signaling playing a role in its development. A study found that reduced autophosphorylation of the PKA-RIIβ subunit is associated with decreased PKA activity and altered neuronal excitability, suggesting it as a potential therapeutic target for TLE.
COMMUNICATIONS BIOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Bingwei Wang, Miao Zhao, Zhijie Su, Baohua Jin, Xiaoning Yang, Chenyu Zhang, Bingbing Guo, Jiebo Li, Weili Hong, Jiarui Liu, Yun Zhao, Yujia Hou, Futing Lai, Wei Zhang, Lihua Qin, Weiguang Zhang, Jianyuan Luo, Ruimao Zheng
Summary: The RII beta subunit of cAMP-dependent protein kinase A (PKA) is expressed in the brain and adipose tissue. RII beta-knockout mice show leanness and increased UCP1 in brown adipose tissue. RII beta reexpression in hypothalamic GABAergic neurons rescues the leanness. The authors investigate the role of RII beta-PKA in white adipose tissue (WAT) browning and find that RII beta-KO mice exhibit robust WAT browning. They also demonstrate that RII beta-PKA in dorsal median hypothalamic GABAergic neurons regulates WAT browning and affects body weight. Targeting RII beta-PKA in DMH GABAergic neurons may have therapeutic potential for obesity and metabolic disorders.
Article
Multidisciplinary Sciences
Isabel Weigand, Cristina L. Ronchi, Jens T. Vanselow, Kerstin Bathon, Kerstin Lenz, Sabine Herterich, Andreas Schlosser, Matthias Kroiss, Martin Fassnacht, Davide Calebiro, Silviu Sbiera
Summary: Mutations in the PRKACA gene are a common cause of cortisol-producing adrenocortical adenomas and Cushing's syndrome, affecting the binding of regulatory subunits and leading to reduced RII β protein levels. The study shows that phosphorylation of RII β at Ser(114) is necessary for its degradation, mediated by caspase 16, resulting in increased cortisol secretion in adrenocortical cells. These findings provide insight into the molecular mechanisms and pathophysiological relevance of R subunit degradation caused by PRKACA mutations in adrenal Cushing's syndrome.
Article
Multidisciplinary Sciences
Sarah G. Cook, Olivia R. Buonarati, Steven J. Coultrap, K. Ulrich Bayer
Summary: The decision between long-term potentiation (LTP) and depression (LTD) in higher brain functions is determined by the complex cross-regulation of T286 and T305/306 autophosphorylation within the 12meric CaMKII holoenzyme. T305/306 phosphorylation selectively promotes LTD while T286 phosphorylation is required for both LTP and LTD. The differential T305/306 phosphorylation directs CaMKII movement to either excitatory or inhibitory synapses, coordinating plasticity at both synapse types.
Review
Cell Biology
Xueyun Hu, Tongyu Gu, Imran Khan, Ahmad Zada, Ting Jia
Summary: Chlorophylls are crucial tetrapyrrole molecules in photosynthesis, undergoing interconversion, turnover, and degradation in response to environmental changes or developmental processes. Research has made significant progress in understanding the metabolic processes of chlorophylls, identifying new pathways and associated enzymes.
Article
Biochemistry & Molecular Biology
Geun Heo, Song-Hee Lee, Ji-Dam Kim, Gyu-Hyun Lee, Jae-Min Sim, Dongjie Zhou, Jing Guo, Xiang-Shun Cui
Summary: This study investigated the function of GRP78 in porcine embryonic development and found that it affects the release of G proteins, subsequently downregulating the cAMP/PKA pathway and influencing CDK1, cyclin B, and mitochondrial function. The results suggest that inhibiting GRP78 function with HA15 treatment may have negative effects on porcine embryo quality and development.
Article
Multidisciplinary Sciences
Shotaro Tsujioka, Ayumi Sumino, Yutaro Nagasawa, Takashi Sumikama, Holger Flechsig, Leonardo Puppulin, Takuya Tomita, Yudai Baba, Takahiro Kakuta, Tomoki Ogoshi, Kenichi Umeda, Noriyuki Kodera, Hideji Murakoshi, Mikihiro Shibata
Summary: CaMKII plays a crucial role in synaptic plasticity and its molecular behavior has been observed using high-speed atomic force microscopy. The dynamic behavior is dependent on CaM binding and pT286 phosphorylation. Rat CaMKIIa exhibited kinase domain oligomerization, which was not observed in other species. Sensitivity to PP2A also differs between the three species.
Article
Biochemistry & Molecular Biology
Inwha Baek, Larry J. Friedman, Jeff Gelles, Stephen Buratowski
Summary: Research shows that in activator-dependent PIC assembly, RNA Pol II, TFIIF, and TFIIE can preassemble on enhancer-bound activators, and multiple RNA Pol II complexes can simultaneously bind to form a localized cluster, while TFIIH binding is unique and depends on the basal promoter.
Article
Biochemistry & Molecular Biology
Kelsey S. Whinn, Zhi-Qiang Xu, Slobodan Jergic, Nischal Sharma, Lisanne M. Spenkelink, Nicholas E. Dixon, Antoine M. van Oijen, Harshad Ghodke
Summary: The accessory helicase Rep in Escherichia coli removes DNA-binding proteins that act as roadblocks to the replication fork, ensuring the smooth progress of genome duplication.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Chemistry, Physical
Dilek Coskun, Wei Chen, Anthony J. Clark, Chao Lu, Edward D. Harder, Lingle Wang, Richard A. Friesner, Edward B. Miller
Summary: Accurate prediction of pKa values of protein residues is crucial for various applications in biology and drug discovery. This study presents a method using free energy perturbation calculations to predict single-protein residue pKa values and develops algorithms to classify residues and identify buried histidines for accurate predictions. A clean data set is defined for testing other pKa prediction methods, and the reported RMSE values indicate good predictive performance.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Biochemistry & Molecular Biology
Beate Bersch, Nicolas Tarbouriech, Wim P. Burmeister, Frederic Iseni
Summary: Poxviruses are enveloped viruses with a linear, double-stranded DNA genome, and viral DNA synthesis is achieved by a DNA polymerase holoenzyme composed of three essential proteins. The catalytic subunit E9 forms a complex with the heterodimeric processivity factor made up of D4 and A20, which have a specific interaction involving a poxvirus-specific insertion. The interface between E9 and A20 comprises conserved hydrophobic residues and has been structurally characterized, providing insights into their molecular interactions.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Medicine, General & Internal
Joan F. Brazier, Fangli Geng, Amy Meehan, Elizabeth M. White, Brian E. McGarry, Renee R. Shield, David C. Grabowski, Momotazur Rahman, Christopher Santostefano, Emily A. Gadbois
Summary: Staffing shortages in US nursing homes during the COVID-19 pandemic have been reported, but quantitative research analyses have found mixed evidence. This qualitative study examines nursing home administrator perspectives to provide context for conflicting reports. The findings show that administrators reported staff shortages and used compensatory strategies to maintain operations, which were supported by quantitative data showing reductions in staff hours, increased use of agency staff, and decreased resident census.
Article
Green & Sustainable Science & Technology
Chun Song, Juan Sesmero, Michael S. Delgado
Summary: The study reveals that the frequency and predictability of turnover among Chinese city officials can affect air quality in their jurisdiction. Air pollution spikes in the year before leadership turnover if the turnover is anticipated, while less frequent turnovers generally lead to lower air pollution. The anticipation effect plays a critical role in understanding the impact of turnover on air quality.
JOURNAL OF CLEANER PRODUCTION
(2021)
Article
Biology
Bin Fan, Dizhi Xie, Yanwei Li, Xulei Wang, Xin Qi, Shuisheng Li, Zining Meng, Xinghan Chen, Junyao Peng, Yongjian Yang, Yuanyou Li, Le Wang
Summary: This study found that the hsd17b1 gene in Oyster pompano has evolved as an MSD gene in the Carangidae family, and a SNP on chromosome 24 is closely associated with phenotypic sex, indicating that hsd17b1 may be a female-determining gene. Different splicing patterns were observed in different genotypes.
PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Bing Liu, Shanshan Li, Yang Liu, Huan Chen, Zhenyue Hu, Zhihao Wang, Yimin Zhao, Lei Zhang, Biyun Ma, Hongliang Wang, Steve Matthews, Yawen Wang, Kaiming Zhang
Summary: Bacterial chromosome replication is catalyzed by DNA polymerase III, with the beta subunits of the clamp-loading complex playing a crucial role in enabling processive DNA replication. Inhibitors targeting the beta-clamp have been explored for antibacterial purposes, while bacteriophages like phage Twort can use proteins like Gp168 to bind to the beta-clamp and halt DNA replication. The cryo-EM structure of the clamp-Gp168 complex reveals a new inhibitory mechanism against beta-clamp function, with potential cross-species implications.
NUCLEIC ACIDS RESEARCH
(2021)
Review
Pharmacology & Pharmacy
Susan S. Taylor, Kristoffer Soberg, Evan Kobori, Jian Wu, Sabine Pautz, Friedrich W. Herberg, Bjorn Steen Skalhegg
Summary: Protein kinase A (PKA) is a holoenzyme consisting of regulatory (R) subunit dimers and two catalytic (C) subunits, with different families of C subunits (Ca and Cb) and four nonredundant R subunits (RIa, RIb, RIIa, RIIb). The N- and C-terminal tails of PKA influence the structure and function of the kinase core, with the Nt-tails showing combinatorial variations in Ca and Cb subunits compared to the conserved Ct-tail. The Cb isoforms, particularly Cb2 in lymphocytes, and Cb3 and Cb4 in the brain, play important and nonredundant roles in PKA signaling, with isoform-specific localization to mitochondria.
MOLECULAR PHARMACOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Leah G. Helton, Hardy J. Rideout, Friedrich W. Herberg, Eileen J. Kennedy
Summary: LRRK2 is a common genetic contributor to Parkinson's disease, with pathogenic mutations often leading to increased kinase activity that can be inhibited by small molecules, but these inhibitors are limited by toxicity. Recent research has focused on protein-protein interactions involving LRRK2 and their role in PD, with potential for constrained peptides and peptidomimetics to target LRRK2.
Meeting Abstract
Biochemistry & Molecular Biology
Jessica H. Bruystens, Jian Wu, Maximilian Wallbott, Daniela Bertinetti, Friedrich W. Herberg, Susan S. Taylor
Article
Multidisciplinary Sciences
Ranjan K. Singh, Ahmed Soliman, Giambattista Guaitoli, Eliza Stoermer, Felix von Zweydorf, Thomas Dal Maso, Asmaa Oun, Laura Van Rillaer, Sven H. Schmidt, Deep Chatterjee, Joshua A. David, Els Pardon, Thomas U. Schwartz, Stefan Knapp, Eileen J. Kennedy, Jan Steyaert, Friedrich W. Herberg, Arjan Kortholt, Christian Johannes Gloeckner, Wim Versees
Summary: Mutations in the LRRK2 gene are a leading cause of Parkinson's disease, while overactivation of LRRK2 is associated with idiopathic form of the disease. Researchers have identified and characterized nanobodies that can bind to different domains of LRRK2 and inhibit or activate its activity. These nanobodies act through an allosteric inhibitor mechanism and provide potential therapeutic strategies for Parkinson's disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Eliza Stoermer, Jui-Hung Weng, Jian Wu, Daniela Bertinetti, Pallavi Kaila Sharma, Wen Ma, Friedrich W. Herberg, Susan S. Taylor
Summary: LRR-kinase 2 (LRRK2) is a protein associated with Parkinson's Disease (PD) and its mutations influence the crosstalk between different domains of LRRK2. The kinase domain drives LRRK2 activation, and the LRR domain and LRR-COR linker hinder substrate binding in the inactive state. Removing the N-terminal domains alters intra-molecular regulation. Hydrogen-Deuterium exchange Mass Spectrometry (HDX-MS) and Gaussian Accelerated Molecular Dynamics (GaMD) techniques provide insights into the conformation and dynamics of different LRRK2 domains, revealing potential therapeutic targets.
BIOCHEMICAL JOURNAL
(2023)
Article
Biochemistry & Molecular Biology
Susan S. Taylor, Friedrich W. Herberg, Gianluigi Veglia, Jian Wu
Summary: Fischer's career primarily focused on protein phosphatases, but he also showed interest in cAMP-dependent protein kinase (PKA) and the high-affinity protein kinase inhibitor (PKI). PKI is a disordered protein that binds tightly to the PKA catalytic subunit with a pseudo-substrate motif. The structure and characteristics of PKI have been studied using different complexes and motifs, including the IP20 motif and the nuclear export signal (NES). PKI and PKA have been found to be highly expressed in the brain and are linked to cancer, but their biological importance in these contexts is not yet fully understood.
Review
Chemistry, Physical
Lalima K. K. Madan, Colin L. L. Welsh, Alexandr P. P. Kornev, Susan S. S. Taylor
Summary: Allosteric regulation of proteins is an engaging research topic that has evolved from focusing on structural changes to considering internal protein dynamics. The violin model, based on redistribution of protein thermal fluctuations, utilizes graph theory and community network analysis to cluster correlated protein motions. This Review provides the theory and workflow of the methodology and illustrates its application to protein kinase A.
JOURNAL OF CHEMICAL PHYSICS
(2023)
Article
Biochemistry & Molecular Biology
Jui-Hung Weng, Chiara R. Trilling, Pallavi Kaila Sharma, Eliza Stoermer, Jian Wu, Friedrich W. Herberg, Susan S. Taylor
Summary: Mutations in the LRRK2 gene increase the risk of Parkinson's disease. LRRK2 is a protein kinase with seven well-folded domains. The LRR-ROC linker becomes disordered when LRRK2 is activated, and a key residue W1295 blocks substrate access. High-dynamics simulations show the stability of the LRR-Linker motif, P + 1 loop, and inhibitory helix.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Article
Chemistry, Medicinal
Brice A. P. Wilson, Ning Li, Juliana A. Martinez Fiesco, Masoumeh Dalilian, Dongdong Wang, Emily A. Smith, Antony Wamiru, Rohan Shah, Ekaterina I. Goncharova, John A. Beutler, Tanja Grkovic, Ping Zhang, Barry R. O'Keefe
Summary: The recent discovery of the oncogenic role of protein kinase A (PKA) in various cancers has revitalized the interest in developing drugs targeting this kinase. Therefore, a series of assays including biochemical, cell-based, and structural biology methods have been established to identify and evaluate new PKA inhibitors. The screening process involved a high-throughput screen of over 200,000 substances, followed by prioritization through biochemical, biophysical, and cell-based assays. Lead compounds with high priority were extensively characterized, which led to the identification of previously unrecognized PKA pharmacophores and the generation of new X-ray crystallography structures demonstrating unique interactions between PKA and inhibitor molecules.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Review
Biochemistry & Molecular Biology
Marie Rumpf, Sabine Pautz, Benedikt Drebes, Friedrich W. W. Herberg, Hans-Arno J. Mueller
Summary: MAST kinases are a conserved branch of the AGC protein kinase superfamily, with four identified family members in mammals. They play a crucial role in various human diseases, including cancer, inflammatory bowel disease, cystic fibrosis, and neuronal disorders. However, the molecular mechanisms of MAST kinases in these diseases are still not well understood.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Arianna Tolone, Wadood Haq, Alexandra Fachinger, Akanksha Roy, Sandeep Kesh, Andreas Rentsch, Sophie Wucherpfennig, Yu Zhu, John Groten, Frank Schwede, Tushar Tomar, Friedrich W. Herberg, Vasilica Nache, Francois Paquet-Durand
Summary: The study found that CN238, a cGMP analogue and PKG inhibitor, can protect photoreceptors and retinal ganglion cells from degeneration, indicating its potential for treating retinal and neurodegenerative diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Riley D. Metcalfe, Juliana A. Martinez Fiesco, Luis Bonet-Ponce, Jillian H. Kluss, Mark R. Cookson, Ping Zhang
Summary: The human leucine-rich repeat kinases (LRRKs), LRRK1 and LRRK2, are large complex kinases that regulate cellular processes and are implicated in human disease. This study reveals the structures of the LRRK1 monomer and dimer using cryo-EM, showing key interdomain interfaces that control kinase activity and structural differences to LRRK2. These findings enhance our understanding of the activation and physiological roles of LRRKs.
NATURE COMMUNICATIONS
(2023)
Article
Biology
Colin L. Welsh, Abigail E. Conklin, Lalima K. Madan
Summary: Understanding the changes in protein shape during cellular function is crucial for understanding biology. In this study, the researchers investigated the protein PKA and how its shape changes as it chemically alters other proteins. Using crystal structures of PKA, they identified regions that change shape based on interactions with ligands or other signaling proteins. These findings provide insight into PKA and protein kinase regulation, which can lead to advances in pharmacological therapies and disease biology.
Meeting Abstract
Biophysics
Colin L. Welsh, Alexandr P. Kornev, Lalima K. Madan
BIOPHYSICAL JOURNAL
(2023)
Meeting Abstract
Medicine, Research & Experimental
Alexandra Fachinger, Zhan Zhou, Misheel Solongo, Philipp Henning, Arianna Tolone, Francois Paquet-Durand, Friedrich W. Herberg
JOURNAL OF TRANSLATIONAL MEDICINE
(2023)