Article
Cell Biology
Dragomir B. Krastev, Shudong Li, Yilun Sun, Andrew Wicks, Gwendoline Hoslett, Daniel Weekes, Luned M. Badder, Eleanor G. Knight, Rebecca Marlow, Mercedes Pardo Calvo, Lu Yu, Tanaji T. Talele, Jiri Bartek, Jyoti Choudhary, Yves Pommier, Stephen J. Pettitt, Andrew Tutt, Kristijan Ramadan, Christopher J. Lord
Summary: The study reveals the regulatory mechanism of trapped PARP1, which is undergoes SUMOylation and ubiquitylation, leading to the recruitment of p97 ATPase for the removal of trapped PARP1 from chromatin and prevention of PARP inhibitor-induced cytotoxicity. Inhibitors targeting p97-complex prolong the trapping of PARP1, enhancing the cytotoxicity of PARP inhibitors in certain types of tumor cells.
NATURE CELL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Pawel P. Szczesniak, Jan B. Heidelberger, Hubert Serve, Petra Beli, Sebastian A. Wagner
Summary: Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by the accumulation of undifferentiated white blood cells in the bone marrow. Inhibition of the molecular chaperone VCP with the inhibitor CB-5083 leads to accumulation of ubiquitylated proteins and triggers apoptosis through the unfolded protein response. This suggests that targeting VCP may be a therapeutic strategy for AML, especially when combined with other drugs. However, further investigation is needed to address the toxicity and development of resistance associated with VCP inhibitors in animal models and clinical trials.
Article
Multidisciplinary Sciences
Shalabh Shukla, Pavlo Lazarchuk, Maria N. Pavlova, Julia M. Sidorova
Summary: D/E repeats are common in human proteins and exhibit genomic stability and specific functional characteristics. They differ from other repeat sequences (such as poly-Q or poly-A) in terms of mutation types and frequencies. D/E repeat proteins preferentially function in chromatin metabolism and their interaction with core histones increases with longer repeat sequences. ATAD2, a D/E repeat protein with unknown function, is frequently overexpressed in tumors.
Article
Multidisciplinary Sciences
Thang Quyet Nguyen, Seri Koh, Jiin Kwon, Soyeon Jang, Wonchull Kang, Jin Kuk Yang
Summary: p97 is a human AAA+ ATPase involved in various cellular processes. METTL21D is a Lys-specific methyltransferase that methylates Lys315 of p97, known as VCPKMT. The structures of S-adenosyl-L-methionine-bound VCPKMT and S-adenosyl-L-homocysteine-bound VCPKMT complexed with p97 N/D1 were reported, revealing the molecular details of p97 recognition and methylation by VCPKMT. The study also investigated the enhancement of p97 methylation through cooperation between VCPKMT and ASPL C-terminus.
Article
Agriculture, Multidisciplinary
Rongxian Hou, Kaihuai Li, Baodian Guo, Yangyang Zhao, Chaohui Li, Bao Tang, Weibo Sun, Bo Wang, Wenchan Chen, Cong Sheng, Jialiang Kan, Yancun Zhao, Fengquan Liu
Summary: This study identified the potential target of heat-stable antifungal factor (HSAF) in fungi and found that HSAF binds to specific sites on VpVeb1, resulting in decreased virulence of V. pyri.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Martin Mistrik, Zdenek Skrott, Petr Muller, Ales Panacek, Lucie Hochvaldova, Katarina Chroma, Tereza Buchtova, Veronika Vandova, Libor Kvitek, Jiri Bartek
Summary: The study introduces a method utilizing plasmonic silver nanoparticles to induce targeted thermal protein damage, allowing for the exploration of cellular stress-response pathways and offering potential therapeutic targets for degenerative diseases.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Arjun Saha, Arieh Warshel
Summary: This study explored the molecular basis of substrate translocation by the AAA+ motor of the 26S proteasome using simulation approaches, revealing the role of electrostatic interactions and validating the involvement of bulkier residues in pore loop 1 in substrate translocation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Sasa Petrovic, Yvette Roske, Biria Rami, Mai Hoang Quynh Phan, Daniela Panakova, Udo Heinemann
Summary: p97 is a crucial AAA+ ATPase that extracts and unfolds substrate proteins. It contributes to various cellular processes and is regulated by adaptor proteins and posttranslational modifications (PTMs). The crystal structure of a p97:ASPL:METTL21D complex reveals how ASPL enables METTL21D to trimethylate p97 at a deeply buried lysine residue.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Oncology
Jieqiong Wang, Yajie Chen, Canhua Huang, Qian Hao, Shelya X. Zeng, Sara Omari, Yu Zhang, Xiang Zhou, Hua Lu
Summary: Valosin-containing protein (VCP) has been identified as a novel regulator of p53-R273H stability, stabilizing p53-R273H through binding to MDM2 and disrupting its association with mutant p53, while inhibition of VCP leads to ubiquitination and degradation of p53-R273H, promoting cell death. VCP may serve as a potential target for the development of pancreatic cancer therapy.
Article
Biochemistry & Molecular Biology
Man Pan, Yuanyuan Yu, Huasong Ai, Qingyun Zheng, Yuan Xie, Lei Liu, Minglei Zhao
Summary: A series of high-resolution cryo-EM structures of substrate-bound human p97 AAA ATPase revealed critical conformational changes and 'power-stroke'-like motions in the ATPase rings, shedding light on the central role of p97 in cellular protein homeostasis. The cryo-EM structure of p97 complexed with the inhibitor NMS-873 at a resolution of 2.4 angstrom demonstrated the mechanism of allosteric inhibition by blocking substrate translocation.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Philip Coffino, Yifan Cheng
Summary: Allostery-regulation at distant sites is a crucial concept in biology, and the proteasome provides multiple examples of this regulation. It can span a long distance, influencing the interactions and assembly of proteasome modules, and explain how diverse populations of proteasome assemblies are built and maintained in cells.
Article
Biochemistry & Molecular Biology
Johannes Van den Boom, Guendalina Marini, Hemmo Meyer, Helen R. Saibil
Summary: In this study, cryo-EM structures were used to reveal the mechanism of AAA+-ATPase p97 in disassembling a protein phosphatase-1 (PP1) complex. The results showed that PP1 and its associated proteins SDS22 and inhibitor-3 (I3) were tightly loaded onto p97 through direct contact with its N-domain, while the p37 adapter bridged two adjacent p97 N-domains underneath the complex. A portion of I3 was threaded into the central channel of the spiral-shaped p97 hexamer, while the rest remained attached to PP1. These findings elucidate how p97 organizes a protein complex and suggest a hold-and-extract mechanism for p97-mediated disassembly.
Article
Chemistry, Multidisciplinary
Ziwen Jiang, Yu-Hsuan Kuo, Mengqi Zhong, Jianchao Zhang, Xin X. Zhou, Lijuan Xing, James A. Wells, Yanzhuang Wang, Michelle R. Arkin
Summary: Protein-protein interactions (PPIs) play crucial roles in cellular signaling and functions. Precise modulation of PPIs can help understand their roles in cellular events and be therapeutically valuable. In this study, an antibody fragment-based modulator for the PPI between p97 and its adaptor protein NSFL1C was developed, demonstrating its potential application in therapeutic interventions by disrupting specific intracellular PPIs.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Multidisciplinary Sciences
Erika Chacin, Priyanka Bansal, Karl-Uwe Reusswig, Luis M. Diaz-Santin, Pedro Ortega, Petra Vizjak, Belen Gomez-Gonzalez, Felix Mueller-Planitz, Andres Aguilera, Boris Pfander, Alan C. M. Cheung, Christoph F. Kurat
Summary: Yta7 is a chromatin remodeling enzyme that promotes chromosome replication during S phase, forming hexameric complexes capable of segregating histones from DNA. Its enzymatic activity is regulated by S phase-forms of Cyclin-Dependent Kinase (S-CDK), which stimulates ATP hydrolysis by Yta7 to promote nucleosome disassembly and chromatin replication. These findings present a mechanism for how cells coordinate chromatin dynamics with the cell cycle machinery to ensure genome duplication during S phase.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Joshua Pajak, Erik Dill, Emilio Reyes-Aldrete, Mark A. White, Brian A. Kelch, Paul J. Jardine, Gaurav Arya, Marc C. Morais
Summary: The study reveals that viral dsDNA packaging motors drive DNA translocation through a process involving ATP binding and hydrolysis events, and this process is achieved through helical-to-planar transitions of the ring motor.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Ricardo J. Aramayo, Oliver Willhoft, Rafael Ayala, Rohan Bythell-Douglas, Dale B. Wigley, Xiaodong Zhang
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2018)
Article
Biochemistry & Molecular Biology
Ricardo J. Aramayo, Oliver Willhoft, Rafael Ayala, Rohan Bythell-Douglas, Dale B. Wigley, Xiaodong Zhang
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2018)
Article
Biology
Oliver Willhoft, Elizabeth A. McCormack, Ricardo J. Aramayo, Rohan Bythell-Douglas, Lorraine Ocloo, Xiaodong Zhang, Dale B. Wigley
Article
Multidisciplinary Sciences
Luke A. Yates, Ricardo J. Aramayo, Nilisha Pokhrel, Colleen C. Caldwell, Joshua A. Kaplan, Rajika L. Perera, Maria Spies, Edwin Antony, Xiaodong Zhang
NATURE COMMUNICATIONS
(2018)
Article
Biology
Fuzhou Ye, Ioly Kotta-Loizou, Milija Jovanovic, Xiaojiao Liu, David T. F. Dryden, Martin Buck, Xiaodong Zhang
Article
Cell Biology
Nicolas Joly, Eva Beaumale, Lucie Van Hove, Lisa Martino, Lionel Pintard
JOURNAL OF CELL BIOLOGY
(2020)
Article
Biology
Griselda Velez-Aguilera, Sylvia Nkombo Nkoula, Batool Ossareh-Nazari, Jana Link, Dimitra Paouneskou, Lucie Van Hove, Nicolas Joly, Nicolas Tavernier, Jean-Marc Verbavatz, Verena Jantsch, Lionel Pintard
Review
Biochemistry & Molecular Biology
Rhys M. Williams, Xiaodong Zhang
Summary: The maintenance of genome integrity is critical for cell survival and genetic information protection, in which ATM and ATR play key roles. While their roles are closely intertwined in response to double strand breaks, they diverge in the response to replication stress.
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Rhys M. Williams, Xiaodong Zhang
Summary: Genome integrity maintenance is crucial for faithful replication and cell protection. ATM and ATR are essential for repair and prevention of DNA damage, with intertwined roles in response to double strand breaks but diverging roles in replication stress. Control of kinase localization and activators allows stress-specific responses.
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY
(2021)
Article
Multidisciplinary Sciences
N. Tavernier, Y. Thomas, S. Vigneron, P. Maisonneuve, S. Orlicky, P. Mader, S. G. Regmi, L. Van Hove, N. M. Levinson, G. Gasmi-Seabrook, N. Joly, M. Poteau, G. Velez-Aguilera, O. Gavet, A. Castro, M. Dasso, T. Lorca, F. Sicheri, L. Pintard
Summary: The research uncovers the activation mechanism of AURKA crucial for mitotic entry, showing that phosphorylated Bora directly activates AURKA kinase activity. Through specific amino acid regions, Bora binds AURKA and substitutes for a key phospho-regulatory site, highlighting the importance of this mechanism for timely mitotic entry in Xenopus and human cells.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Jessica Knox, Nicolas Joly, Edmond M. Linossi, Jose A. Carmona-Negron, Natalia Jura, Lionel Pintard, William Zuercher, Peter J. Roy
Summary: Over one billion people are currently infected with a parasitic nematode, leading to various symptoms. Resistance is emerging to current anthelmintics, prompting the need for new drugs. Studies have identified nematode EGFR, MEK1, and PLK1 as potential key targets for the development of new anthelmintics.
SCIENTIFIC REPORTS
(2021)
Article
Multidisciplinary Sciences
Fuzhou Ye, Forson Gao, Xiaojiao Liu, Martin Buck, Xiaodong Zhang
Summary: Gene transcription requires DNA melting and opening to form transcription initiation complexes. In bacteria, this process is mediated by RNA polymerase (RNAP) and sigma factors. A study found that a specific sigma factor (sigma(54)) interacts with an AAA+ activator to facilitate DNA melting and opening.
Article
Multidisciplinary Sciences
Luke A. Yates, Elias A. Tannous, R. Marc Morgan, Peter M. Burgers, Xiaodong Zhang
Summary: This study reveals the phosphorylation circuit that regulates checkpoint recruitment and function in response to DNA damage. The interaction between Ddc2 and RPA modulates the association between RPA and ssDNA, and phosphorylated Ddc2 enhances its recruitment to RPA-ssDNA, promoting DNA damage checkpoint signaling.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Elias A. Tannous, Luke A. Yates, Xiaodong Zhang, Peter M. Burgers
Summary: A mutation in Mec1 leading to constitutive activity was identified, and structural analysis revealed the molecular basis for Mec1 activation and key regulatory mechanisms through conformational changes.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2021)
Article
Cell Biology
Lisa Martino, Stephanie Morchoisne-Bolhy, Dhanya K. Cheerambathur, Lucie Van Hove, Julien Dumont, Nicolas Joly, Arshad Desai, Valerie Doye, Lionel Pintard
DEVELOPMENTAL CELL
(2017)
Article
Biochemistry & Molecular Biology
Ankita Chadda, Alexander G. Kozlov, Binh Nguyen, Timothy M. Lohman, Eric A. Galburt
Summary: In this study, it was found that the DNA damage response in Mycobacterium tuberculosis differs from well-studied model bacteria. The DNA repair helicase UvrD1 in Mtb is activated through a redox-dependent process and is closely associated with the homo-dimeric Ku protein. Additionally, Ku protein is shown to stimulate the helicase activity of UvrD1.
JOURNAL OF MOLECULAR BIOLOGY
(2024)