Article
Biochemical Research Methods
Jordane Preto, Isabelle Krimm
Summary: The voltage-dependent anion channel (VDAC) is a critical membrane protein in the mitochondrial outer membrane that regulates ion and ATP transport while playing a key role in apoptosis. The N-terminus of VDAC is an intrinsically disordered region that significantly impacts its gating mechanism, providing new insights into the dynamics of the channel.
PLOS COMPUTATIONAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Hana Popelka, Vikramjit Lahiri, Wayne D. Hawkins, Felipe da Veiga Leprevost, Alexey I. Nesvizhskii, Daniel J. Klionsky
Summary: The intrinsically disordered protein region (IDPR) of Atg12 protein plays an important role in its functional structure, as it is positioned in proximity to the ubiquitin-like (UBL) domain. Deletion in IDPR disrupts the integrity of the UBL domain, while a mutation in the predicted α0 helix in IDPR prevents Atg12 from binding to Atg7 and Atg10, impacting its function in the ubiquitin-like conjugation cascade.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Mao Zhang, Cheng Zhu, Yuanyuan Duan, Tongbao Liu, Haoping Liu, Chang Su, Yang Lu
Summary: A unique group of PP2C phosphatases from fungi and plants have been found to sense CO2, but not HCO3-, to control diverse cellular programmes. They have intrinsically disordered regions (IDR) that form reversible liquid-like droplets through phase separation and are activated in response to elevated environmental CO2 in an IDR-dependent manner.
NATURE CELL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Emilie Aponte, Marie Lafitte, Audrey Sirvent, Valerie Simon, Maud Barbery, Elise Fourgous, Mariano Maffei, Florence Armand, Romain Hamelin, Julie Pannequin, Philippe Fort, Miquel Pons, Serge Roche, Yvan Boublik
Summary: This study reveals the important role of the unique domain ULBR in Src tyrosine kinase in malignant cell transformation. The ULBR is involved in membrane anchoring, MAPK signaling, and phosphorylation of specific membrane-localized tyrosine kinases needed for Src oncogenic signaling.
Review
Biochemistry & Molecular Biology
Goro Kato
Summary: This review discusses the structural and functional aspects of Src protein and its regulatory mechanism. By reviewing nuclear magnetic resonance analyses and recent studies, the authors explore new characteristics and regulatory roles of Src protein. Finally, the new regulatory roles are integrated with the canonical model to elucidate the functions of full-length Src.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Guanlan Fan, Fan Wang, Yurou Chen, Qian Zheng, Jie Xiong, Qiongying Lv, Kejia Wu, Jiaqiang Xiong, Lei Wei, Dongqing Li, Jiachen Zhang, Wei Zhang, Feng Li
Summary: In this study, OTUD1 is identified as an Akt-associated protein and is downregulated upon Akt activation. Ectopic OTUD1 inhibits Akt phosphorylation, and a short peptide (OUN-36) located in the OTUD1 N-terminal intrinsically disordered region strongly binds to the Akt PH domain. OUN-36-based therapy efficiently abrogates Akt feedback reactivation and sensitizes cancer cells to chemotherapy and immunotherapy.
Article
Multidisciplinary Sciences
Jie Heng, Yunfei Hu, Guillermo Perez-Hernandez, Asuka Inoue, Jiawei Zhao, Xiuyan Ma, Xiaoou Sun, Kouki Kawakami, Tatsuya Ikuta, Jienv Ding, Yujie Yang, Lujia Zhang, Sijia Peng, Xiaogang Niu, Hongwei Li, Ramon Guixa-Gonzalez, Changwen Jin, Peter W. Hildebrand, Chunlai Chen, Brian K. Kobilka
Summary: Research reveals the dynamic behavior of the beta 2 adrenergic receptor C-terminus and its autoinhibitory function in downstream Gs coupling.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Stefan Schuetz, Christian Bergsdorf, Benedikt Goretzki, Andreas Lingel, Martin Renatus, Alvar D. Gossert, Wolfgang Jahnke
Summary: This study utilizes Nuclear Magnetic Resonance (NMR) spectroscopy and Surface Plasmon Resonance (SPR) to investigate the interactions between the proteins MYC and MAX, and their roles in regulating cellular processes.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
H. Jane Dyson
Summary: Viruses infect all kingdoms of life and employ disordered proteins to accomplish various functions. Disordered proteins have been discovered in almost all viruses studied, regardless of the viral genome composition or the viral capsid configuration. This review presents a collection of stories illustrating the diverse functions of disordered proteins in viruses, providing a survey of the field's expansion.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Kento Shimakura, Kai Sato, Shun Mitsui, Suzuka Ono, Asako Otomo, Shinji Hadano
Summary: The results indicate that the intrinsically disordered region (IDR) of ALS2 plays a crucial role in the regulation of intracellular localization and self-oligomerization of ALS2 in cells, while the phosphorylation of certain residues within the IDR has limited effects on such phenotypes.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Virology
Satyamurthy Kundharapu, Tirumala Kumar Chowdary
Summary: Dengue virus replication relies on interactions between NS proteins, with the NS4b-NS3 interaction enhancing helicase activity. The N-terminal region of NS4b interacts with NS3, wrapping around the C-terminal subdomain of the helicase and influencing its activity.
Article
Biology
Khanh Dinh Quoc Nguyen, Michael Vigers, Eric Sefah, Susanna Seppala, Jennifer Paige Hoover, Nicole Star Schonenbach, Blake Mertz, Michelle Ann O'Malley, Songi Han
Summary: The intrinsically disordered C-terminus of the human adenosine A(2A) receptor (A(2A)R) is found to be a prominent driving factor for receptor homo-oligomerization. A(2A)R oligomer formation decreases progressively with the shortening of the C-terminus, with multiple interaction types contributing to the oligomerization, including disulfide linkages, hydrogen bonds, electrostatic interactions, and hydrophobic interactions. These interactions are enhanced by depletion interactions, creating a tunable network of bonds for A(2A)R oligomers to adopt multiple interfaces.
Article
Cell Biology
Meghan T. Harris, Michael T. Marr II
Summary: Cells activate stress response pathways to survive adverse conditions by inhibiting global translation and utilizing alternative methods of translation initiation, such as IRES. Cellular IRESs have been identified in many stress response transcripts. eIF5B promotes IRES activity through its N-terminal region via a non-canonical mechanism.
Article
Multidisciplinary Sciences
Rebecca B. Berlow, H. Jane Dyson, Peter E. Wright
Summary: Intrinsically disordered proteins compete for binding to common regulatory targets to carry out their biological functions. The activation domains of HIF-1 alpha and CITED2 function as a unidirectional, allosteric molecular switch to control transcription of adaptive genes. The mechanistic details of this molecular switch were characterized through NMR spectroscopy and biophysical methods, revealing the contributions of individual binding motifs in CITED2. These findings provide insight into the complexity of molecular interactions involving disordered proteins and how they compete for occupancy of common targets.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Biochemistry & Molecular Biology
Tanuj Handa, Debanjan Kundu, Vikash Kumar Dubey
Summary: The importance of protein structure in performing biological functions optimally is being challenged by the emergence of intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs). Understanding the evolutionary and functional significance of these proteins is crucial in studying various organisms. This review highlights the importance of IDPs in the physiology of specific organisms and establishes a positive correlation between IDPs and their relevance in human health and future medicine. Extensive research on IDPs and IDPRs will greatly contribute to expanding the field of structural biology, aiding in the comprehension of protein folding, misfolding, associated diseases, and drug design.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Biochemistry & Molecular Biology
Stefanie M. Bader, Simon P. Preston, Katie Saliba, Adam Lipszyc, Zoe L. Grant, Liana Mackiewicz, Andrew Baldi, Anne Hempel, Michelle P. Clark, Thanushi Peiris, William Clow, Jan Bjelic, Michael D. Stutz, Philip Arandjelovic, Jack Teale, Fashuo Du, Leigh Coultas, James M. Murphy, Cody C. Allison, Marc Pellegrini, Andre L. Samson
Summary: Caspase-8 mediates various responses including inflammation, cell proliferation, and cell death. Its function during embryogenesis is essential for maintaining systemic circulatory system, while in adulthood it is crucial for preserving gut vascular integrity. Lack of endothelial Caspase-8 leads to fatal hemorrhagic lesions in the small intestine, resulting from aberrant microbial sensing and tumor necrosis factor receptor signaling.
CELL DEATH AND DIFFERENTIATION
(2023)
Review
Cell Biology
Christopher R. Horne, Andre L. Samson, James M. Murphy
Summary: In the past decade, the importance of the necroptosis programmed cell death pathway in the pathophysiology of various diseases has been confirmed. The receptor interacting protein kinase (RIPK)1 and RIPK3, and the pseudokinase executioner protein, mixed lineage kinase domain-like (MLKL), have emerged as core components of the pathway. These proteins also serve as integrators of signals and add complexity to pathway regulation. This article describes the emerging concept of the protein network that tunes necroptotic signal transduction and how these events have diverged across species, possibly due to selective pressures from pathogens on the RIPK3-MLKL protein pair.
TRENDS IN CELL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Sebastian A. Hughes, Meng Lin, Ashley Weir, Bing Huang, Liya Xiong, Ngee Kiat Chua, Jiyi Pang, Jascinta P. Santavanond, Rochelle Tixeira, Marcel Doerflinger, Yexuan Deng, Chien-Hsiung Yu, Natasha Silke, Stephanie A. Conos, Daniel Frank, Daniel S. Simpson, James M. Murphy, Kate E. Lawlor, Jaclyn S. Pearson, John Silke, Marc Pellegrini, Marco Herold, Ivan K. H. Poon, Seth L. Masters, Mingsong Li, Qin Tang, Yuxia Zhang, Maryam Rashidi, Lanlan Geng, James E. Vince
Summary: This study reveals that genetic mutations in X-linked inhibitor of apoptosis (XIAP) can lead to cell death-associated inflammatory diseases. The findings show that patients with XIAP deficiency-associated inflammatory bowel disease have increased inflammatory IL-1 beta maturation and cell death-associated caspase-8 and Gasdermin D (GSDMD) processing, which can be reduced by patient treatment.
Article
Medicine, Research & Experimental
Sanjeevini Babu Reddiar, Michael de Veer, Brett M. Paterson, Tara Sepehrizadeh, Dorothy C. C. Wai, Agota Csoti, Gyorgy Panyi, Joseph A. Nicolazzo, Raymond S. Norton
Summary: This study investigates the in vivo distribution of HsTX1[R14A] peptide in mice and finds increased uptake in a LPS-induced mouse model of neuroinflammation, as well as accumulation in inflamed joints.
MOLECULAR PHARMACEUTICS
(2023)
Review
Urology & Nephrology
Benedikt Kolbrink, Friedrich A. von Samson-Himmelstjerna, James M. Murphy, Stefan Krautwald
Summary: Cell death, particularly tubule epithelial cell death, plays a critical role in the pathophysiology of kidney disease. Accumulated evidence has shown that necroptosis, a form of regulated necrosis, is involved in acute tubular necrosis, nephron loss, and renal fibrogenesis. Unlike apoptosis, necroptosis triggers an inflammatory response due to the release of cellular contents and cytokines. Despite the link between necroptosis and kidney diseases, therapeutic options targeting this process are currently unavailable. Further understanding of the molecular mechanisms and regulators of necroptosis may lead to innovative therapeutic approaches.
NATURE REVIEWS NEPHROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Hao Chen, Nghi H. Nguyen, Charlene M. Magtoto, Simon A. Cobbold, Grace M. Bidgood, Lizeth G. Meza Guzman, Lachlan W. Richardson, Jason Corbin, Amanda E. Au, Bernhard C. Lechtenberg, Rebecca Feltham, Kate D. Sutherland, Christoph Grohmann, Sandra E. Nicholson, Brad E. Sleebs
Summary: A proteolysis targeting chimera (PROTAC) that depletes KEAP1 and activates the NRF2 antioxidant response has been developed as a potential strategy to treat diseases caused by oxidative stress. The optimized PROTAC 14 demonstrated potent KEAP1 degradation and increased expression of antioxidant proteins, effectively preventing cell death induced by reactive oxygen species. This approach presents an alternative therapeutic strategy for oxidative stress-related diseases.
Article
Chemistry, Medicinal
Karoline Sanches, Viktor Prypoten, K. George Chandy, David K. Chalmers, Raymond S. Norton
Summary: Peptide toxins like ShK can inhibit the KV1.3 potassium channel and may have potential therapeutic applications for autoimmune and neuroinflammatory diseases. ShK and its homolog HmK exhibit different dynamic behaviors, with ShK showing higher affinity for the KV1.3 channel.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Christopher R. Gardner, Katherine A. Davies, Ying Zhang, Martin Brzozowski, Peter E. Czabotar, James M. Murphy, Guillaume Lessene
Summary: Necroptosis is a regulated caspase-independent form of necrotic cell death that leads to an inflammatory phenotype. It plays a significant role in the pathophysiology of various diseases. The key components of necroptosis signaling, such as RIPK1, RIPK3, and MLKL, have been identified, and they hold promise as therapeutic targets.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Yue R. Pan, Indu Chandrashekaran, Luke Tennant, Jamie Rossjohn, Dene Littler
Summary: Nsp9 is an important component in coronaviral replication and transcription complex. It facilitates nucleotidylation activity of nsp12 and recruits proteins necessary for viral 5'-capping. Antibodies targeting nsp9 can induce significant changes in its overall structure and dynamics, particularly in the cavity between s2-s3 and s4-s5 loops and the C-terminal GxxxG helix.
Article
Food Science & Technology
Hayden L. Smith, Peter J. Prentis, Scott E. Bryan, Raymond S. Norton, Daniel A. Broszczak
Summary: The venom delivery system of Phylum Cnidaria is unique, consisting of individual organelles known as nematocysts. Acontia, found in a limited number of sea anemone species, are packed with large nematocysts used for defense. This study identified the venom profile of acontia in Calliactis polypus, revealing limited toxin diversity and a novel toxin with two ShK-like domains. This research provides a foundation for further investigating the function of acontial toxins in sea anemones.
Review
Biochemistry & Molecular Biology
K. George Chandy, Karoline Sanches, Raymond S. Norton
Summary: The voltage-gated potassium channel K(V)1.3 is an important therapeutic target for autoimmune and neuroinflammatory diseases. Recent structural studies have provided insights into the conformational changes of the channel and the mechanism of ion permeation. These findings contribute to a better understanding of the slow inactivation mechanism of K(V) channels and can guide the development of future immunotherapeutics targeting K(V)1.3.
Article
Biochemistry & Molecular Biology
Karoline Sanches, Lauren M. Ashwood, Abisola Ave-Maria Olushola-Siedoks, Dorothy C. C. Wai, Arfatur Rahman, Kashmala Shakeel, Muhammad Umair Naseem, Gyorgy Panyi, Peter J. Prentis, Raymond S. Norton
Summary: Diverse structural scaffolds have been found in peptides from sea anemones, including the common ShKT scaffold. While some ShKT peptides from sea anemones inhibit K-V 1.x channels, others do not. Using NMR and molecular dynamics simulations, a new ShKT peptide from the sea anemone Telmatactis stephensoni was studied and found to have no activity against K-V 1.x channels. The exposure of dyad residues during MD simulations is correlated with the ability of ShKT peptides to block K-V 1.x channels.
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
(2023)
Article
Multidisciplinary Sciences
Shuwei Liang, Eric Tran, Xin Du, Jiajun Dong, Harrison Sudholz, Hao Chen, Zihan Qu, Nicholas D. Huntington, Jeffrey J. Babon, Nadia J. Kershaw, Zhong-Yin Zhang, Jonathan B. Baell, Florian Wiede, Tony Tiganis
Summary: In this study, the authors demonstrate that inhibition of PTP1B and PTPN2 in tumor cells and T cells with a small molecule inhibitor represses the growth of immunogenic and cold tumors, and enhances response to anti-PD-1 immunotherapy without promoting immune-related toxicities.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Rebecca L. L. Whitehouse, Wesam S. S. Alwan, Olga V. V. Ilyichova, Ashley J. J. Taylor, Indu R. R. Chandrashekaran, Biswaranjan Mohanty, Bradley C. C. Doak, Martin J. J. Scanlon
Summary: Fragment-based drug design relies on structural information obtained through X-ray crystallography to evolve fragments into lead-like compounds through structure-based design. The composition of compound libraries can be optimized to probe binding hot spots on protein surfaces.
RSC MEDICINAL CHEMISTRY
(2023)
