Article
Virology
Airah Javorsky, Patrick O. Humbert, Marc Kvansakul
Summary: Scribble is a crucial regulator of cell polarity during viral infections. The NS1 protein of influenza virus can target Scribble PDZ domains and disrupt the normal control of cell polarity. The study characterizes the binding affinities of different NS1 PDZ binding motifs to Scribble PDZ domains and provides insights into the structural basis of their interactions.
Article
Biochemistry & Molecular Biology
Airah Javorsky, Janesha C. Maddumage, Emily R. R. Mackie, Tatiana P. Soares da Costa, Patrick O. Humbert, Marc Kvansakul
Summary: Scribble is a crucial regulator of cell polarity that interacts with Tax1 and disrupts cell polarity signaling, potentially promoting tumorigenesis.
Article
Multidisciplinary Sciences
Marilyn Goudreault, Valerie Gagne, Chang Hwa Jo, Swati Singh, Ryan C. Killoran, Anne-Claude Gingras, Matthew J. Smith
Summary: Goudreault et al. investigate the role of Afadin as a genuine effector of RAS GTPases, showing its association with cell polarity through Scribble protein. AFDN is essential for cell-cell contacts and has broad specificity for RAS and RAP GTPases. The study also reveals the interaction between the first PDZ domain of SCRIB and the FHA domain of AFDN, and demonstrates the importance of AFDN and SCRIB in MAPK and PI3K activation kinetics and cell motility.
NATURE COMMUNICATIONS
(2022)
Review
Biochemistry & Molecular Biology
Airah Javorsky, Patrick O. Humbert, Marc Kvansakul
Summary: Cell polarity refers to the asymmetric distribution of biomacromolecules that enable correct orientation of a cell. Viral infections can lead to dysregulation of polarity by interfering with cell polarity regulatory proteins. Understanding viral effector proteins' mechanisms of action on cell polarity can lead to therapeutic interventions and enhance our understanding of tissue homeostasis.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2023)
Review
Biochemistry & Molecular Biology
Airah Javorsky, Patrick O. Humbert, Marc Kvansakul
Summary: Scribble is a scaffolding protein that regulates cell polarity, tumorigenesis and neuronal signalling. It interacts with viral effector proteins, leading to dysregulation of cell signalling pathways. This review focuses on the molecular details of Scribble and viral effector proteins interaction and provides insights into the regulation of Scribble-mediated polarity signalling.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2023)
Article
Medicine, General & Internal
Ioannis A. Voutsadakis
Summary: Alterations in the planar cell polarity (PCP) pathway genes can be observed in breast cancers, particularly in the basal subtype. Two breast cancer cell line models with amplifications in PCP genes display sensitivity to inhibitors of acyl-transferase porcupine, suggesting these inhibitors may be potential candidates for combination therapy in PCP-altered breast cancers.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Cell Biology
Sarannya Edamana, Frederic H. Login, Andreas Riishede, Vibeke S. Dam, Trine Tramm, Lene N. Nejsum
Summary: Breast carcinomas are associated with increased cell proliferation, migration, altered cellular adhesion, and loss of epithelial polarity. Aquaporin-5 (AQP5) is aberrantly expressed in breast cancer and is linked to metastasis and poor prognosis. AQP5 enhances cancer cell proliferation and migration, reduces cell-cell adhesion, and activates the Ras pathway. This study explores the relationship between AQP5 and the polarity protein Scribble. Results show that high AQP5 expression is inversely related to Scribble levels in breast carcinoma tissue samples. Overexpression of AQP5 in breast cancer cells reduces spheroid size, circularity, and Scribble levels. The effect of AQP5 on Scribble is partially dependent on AQP5-mediated activation of Ras. These findings suggest that AQP5 negatively regulates cellular polarity in breast cancer.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2023)
Article
Biology
Eva-Maria Thuering, Christian Hartmann, Janesha C. Maddumage, Airah Javorsky, Birgitta E. Michels, Volker Gerke, Lawrence Banks, Patrick O. Humbert, Marc Kvansakul, Klaus Ebnet
Summary: The protein Scribble binds the cell adhesion receptor TMIGD1 and is recruited to the lateral membrane of polarized epithelial cells. The interaction between Scribble and TMIGD1 is important for the membrane localization of Scribble and its tumor-suppressive activity.
COMMUNICATIONS BIOLOGY
(2023)
Article
Crystallography
Ma Carmen Salinas-Garcia, Marina Plaza-Garrido, Jose A. A. Gavira, Javier Murciano-Calles, Montserrat Andujar-Sanchez, Emilia Ortiz-Salmeron, Jose C. C. Martinez, Ana Camara-Artigas
Summary: The PDZ domains can recognize short linear C-terminal sequences in proteins, facilitating the formation of complex multi-component structures. Crystals of the third PDZ domain of PSD95 were obtained at mildly acidic pH, resulting in four different polymorphs. The polymorphs exhibit different crystal shapes and share a common crystallographic interface. Analysis of these polymorphs provides insights into the importance of specific protein-protein interactions in protein crystallization.
Article
Immunology
Fang Zheng, Jinhong Zhou, Zhenlin Ouyang, Jiaxin Zhang, Xinyi Wang, Serge Muyldermans, Jo Van Ginderachter, Nick Devoogdt, Yurong Wen, Steve Schoonooghe, Geert Raes
Summary: Nanobodies derived from camelids have been developed targeting the Kupffer cell-specific receptor Clec4F, with a strong affinity and the ability to specifically target the liver. Structural characterization revealed distinct features within the CDR2 and CDR3 regions of the nanobodies, indicating different recognition epitopes.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Seri Jo, Hwa Young Kim, Dong Hae Shin, Mi-Sun Kim
Summary: 3CLpro of SARS-CoV-2 is a potential target for anti-COVID-19 agents development. The catalytic activity of 3CLpros was evaluated in two forms, with or without the dimerization domain. The crystal structure analysis revealed that the catalytic domain alone has lower enzymatic activity compared to the full domain, attributed to incomplete construction of the substrate binding part. Furthermore, SARS-CoV families showed conformational differences in the interaction between DM-loop and helix alpha 7. This new insight provides useful information for understanding the behavior of SARS-CoV-2 3CLpro and developing anti-COVID-19 agents.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Joseph P. Campanale, James A. Mondo, Denise J. Montell
Summary: Collective cell movements play a critical role in normal development and metastasis. This study unveils the role of Rac GTPase and its regulator Cdep in driving migration and cluster movement in Drosophila border cells.
DEVELOPMENTAL CELL
(2022)
Article
Physics, Applied
Jong Woo Kim, Mathew J. Cherukara, Ashish Tripathi, Zhang Jiang, Jin Wang
Summary: Coherent surface scattering imaging requires a mathematical conversion to visualize specimen structures, which can now be predicted using a deep learning neural network model to instantly obtain results from scattering patterns. This is highly beneficial for both experimental effectiveness and data analysis.
APPLIED PHYSICS LETTERS
(2021)
Article
Chemistry, Multidisciplinary
Cen Chen, Ziyuan Fang, Zhen Huang
Summary: Crystallization phasing and obtaining high-quality crystals are major challenges for X-ray crystallographic analysis of nucleic acids. In this study, the authors addressed these challenges by incorporating selenium atoms into DNA duplexes, which resulted in larger and higher quality crystals compared to standard DNA crystals. These findings provide a simple strategy to overcome crystallization challenges in nucleic acid crystallography.
CRYSTAL GROWTH & DESIGN
(2022)
Article
Multidisciplinary Sciences
Akimitsu Higuchi, Wataru Shihoya, Masae Konno, Tatsuya Ikuta, Hideki Kandori, Keiichi Inoue, Osamu Nureki
Summary: SzRs, a newly identified rhodopsin family in Asgard archaea, exhibit unique kinetic behaviors in inward H+ release compared to other H+ pumps. The crystal structure of SzR AM_5_00977 revealed that key residues and structural features are different from other microbial rhodopsins, suggesting a distinct mechanism for inward H+ release.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Patrick O. Humbert, Tamara Zoranovic Pryjda, Blanka Pranjic, Andrew Farrell, Kohei Fujikura, Ricardo de Matos Simoes, Rezaul Karim, Ivona Kozieradzki, Shane J. F. Cronin, G. Gregory Neely, Thomas F. Meyer, Astrid Hagelkruys, Helena E. Richardson, Josef M. Penninger
Summary: This study identifies TSPAN6 as a tumor suppressor receptor that controls the initiation and progression of RAS-driven epithelial cancer. TSPAN6 suppresses tumor growth and metastasis by blocking EGFR-induced RAS activation.
Article
Multidisciplinary Sciences
Pei Kee Goh, Florian Wiede, Mara N. Zeissig, Kara L. Britt, Shuwei Liang, Tim Molloy, Nathan Goode, Rachel Xu, Sherene Loi, Mathias Muller, Patrick O. Humbert, Catriona McLean, Tony Tiganis
Summary: The tumor-suppressor gene PTPN2 is often diminished in a specific type of breast cancer. Surprisingly, the absence of PTPN2 in tumors or T cells can actually promote the recruitment and activation of T cells, leading to enhanced anti-tumor immunity. Targeting PTPN2 in tumor cells and T cells has therapeutic potential, as PTPN2 deficiency is associated with T cell infiltration and increased expression of PD-L1 in triple-negative breast cancers (TNBCs). Furthermore, deleting PTPN2 in mouse TNBC models can enhance T cell recruitment and PD-L1 expression, leading to suppressed tumor growth and improved efficacy of anti-PD-1 treatment. Additionally, deleting PTPN2 in both tumors and T cells can further facilitate T cell recruitment and activation, resulting in repression of tumor growth or even elimination of tumors dominated by exhausted T cells. Therefore, targeting PTPN2 in tumors and/or T cells can enhance T cell recruitment and alleviate inhibitory effects on T cells to combat TNBC.
Article
Biochemistry & Molecular Biology
Chathura D. Suraweera, Suresh Banjara, Mark G. Hinds, Marc Kvansakul
Summary: The B-cell lymphoma-2 (Bcl-2) family of genes regulates intrinsic apoptosis by coordinating the integrity of the mitochondrial outer membrane. Bcl-2 genes are present in early metazoans and have different variations among species. The structure of Bcl-2 proteins is highly conserved over evolutionary time, and some Bcl-2 proteins may have non-apoptotic functions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Correction
Biochemistry & Molecular Biology
Patrick O. Humbert, Tamara Zoranovic Pryjda, Blanka Pranjic, Andrew Farrell, Kohei Fujikura, Ricardo de Matos Simoes, Rezaul Karim, Ivona Kozieradzki, Shane J. F. Cronin, G. Gregory Neely, Thomas F. Meyer, Astrid Hagelkruys, Helena E. Richardson, Josef M. Penninger
Article
Virology
Airah Javorsky, Patrick O. Humbert, Marc Kvansakul
Summary: Scribble is a crucial regulator of cell polarity during viral infections. The NS1 protein of influenza virus can target Scribble PDZ domains and disrupt the normal control of cell polarity. The study characterizes the binding affinities of different NS1 PDZ binding motifs to Scribble PDZ domains and provides insights into the structural basis of their interactions.
Article
Biochemistry & Molecular Biology
Airah Javorsky, Patrick O. Humbert, Marc Kvansakul
Summary: The study found that the interaction between the NS5 protein of TBEV and Scribble protein is through the PDZ3 domain of Scribble, contrary to the previous hypothesis. By determining the structural basis, these interactions provide a platform for studying the pathogenesis of TBEV and cell polarity signaling.
BIOCHEMICAL JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Airah Javorsky, Janesha C. Maddumage, Emily R. R. Mackie, Tatiana P. Soares da Costa, Patrick O. Humbert, Marc Kvansakul
Summary: Scribble is a crucial regulator of cell polarity that interacts with Tax1 and disrupts cell polarity signaling, potentially promoting tumorigenesis.
Article
Virology
Chathura D. Suraweera, Mark G. Hinds, Marc Kvansakul
Summary: Apoptosis is a defense mechanism used by multicellular organisms to counteract viral infection. Viruses have evolved various countermeasures to ensure cell viability and optimize their replication. In this study, the crystal structures of Epstein-Barr virus (EBV)-encoded BHRF1 bound to proapoptotic proteins Bid and Puma were determined. BHRF1 engages with BH3 peptides using its Bcl-2 fold and mimics the canonical ionic interaction seen in host Bcl-2:BH3 complexes. Furthermore, Bid and Puma utilize a distinct hydrophobic interaction with BHRF1. These findings provide insights into EBV-mediated inhibition of host cell apoptosis and the flexibility of virus-encoded Bcl-2 proteins in mimicking key interactions from the host signaling pathways.
Article
Biology
Anchi S. Chann, Mirren Charnley, Lucas M. Newton, Andrea Newbold, Florian Wiede, Tony Tiganis, Patrick Humbert, Ricky W. Johnstone, Sarah M. Russell
Summary: During T cell development, the process of TCR β chain genetic recombination is crucial. In this study, the selective inhibitor ACY1215 disrupted the fate determination at the beta-selection checkpoint, revealing a new stage characterized by the up-regulation of TCR co-receptors CD28 and CD2. Additionally, the up-regulation of CD5 and Lef1 during this stage reflects pre-TCR signaling and correlates with proliferation. These findings provide a refined model of beta-selection and highlight the importance of coordinated gene expression.
LIFE SCIENCE ALLIANCE
(2022)
Review
Biochemistry & Molecular Biology
Airah Javorsky, Patrick O. Humbert, Marc Kvansakul
Summary: Scribble is a scaffolding protein that regulates cell polarity, tumorigenesis and neuronal signalling. It interacts with viral effector proteins, leading to dysregulation of cell signalling pathways. This review focuses on the molecular details of Scribble and viral effector proteins interaction and provides insights into the regulation of Scribble-mediated polarity signalling.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2023)
Meeting Abstract
Hematology
Lucas M. Newton, Christina B. Wolwer, Krystle Lim, Edwin D. Hawkins, Patrick O. Humbert
Article
Cell Biology
Anchi S. Chann, Ye Chen, Tanja Kinwel, Patrick O. Humbert, Sarah M. Russell
Summary: The regulation of daughter cell positioning involves the cooperation of polarity protein Scribble and E-cadherin. Scribble stabilizes E-cadherin and mediates spindle orientation, and then relocates to facilitate the formation of a new E-cadherin-based interface between the daughters, influencing cell positioning.
JOURNAL OF CELL SCIENCE
(2023)
Article
Multidisciplinary Sciences
Bryce Z. Stewart, Tatyana Mamonova, W. Bruce Sneddon, Airah Javorsky, Yanmei Yang, Bin Wang, Thomas D. Nolin, Patrick O. Humbert, Peter A. Friedman, Marc Kvansakul
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)