Article
Biochemistry & Molecular Biology
Jian Yang, Luis A. R. Carvalho, Shanping Ji, Suyuan Chen, Rui Moreira, Steven H. L. Verhelst
Summary: In this study, 4-oxo-beta-lactams are identified as a novel scaffold for inhibition of rhomboid proteases, and they may serve as both inhibitors and activity-based probes for rhomboid proteases.
Article
Microbiology
Maria Ines Marchesini, Ansgar Poetsch, Leticia Soledad Guidolin, Diego J. Comerci
Summary: Rhomboids are intramembrane serine proteases highly conserved in all life domains. The study showed that Brucella abortus encodes an active rhomboid protease capable of cleaving heterologous substrates. Deletion of rhomboid had no significant impact on B. abortus virulence, but overexpression had negative effects on growth.
Article
Biology
Sandra Olenic, Lim Heo, Michael Feig, Lee Kroos
Summary: This study reveals a novel mechanism of inhibition for intramembrane proteases, which has implications for relief from inhibition in vivo and the design of potential therapeutic inhibitors.
Article
Chemistry, Medicinal
William H. Parsons, Nicholas T. Rutland, Jennifer A. Crainic, Joaquin M. Cardozo, Alyssa S. Chow, Charlotte L. Andrews, Brendan K. Sheehan
Summary: Using activity-based protein profiling technology, we identified a series of sulfonyl esters and sulfonamides as inhibitors of the mitochondrial rhomboid protease PARL. These compounds showed high selectivity for PARL over the bacterial rhomboid protease GlpG. The reversible binding of these compounds to PARL in mammalian cells suggests their potential as PARL-selective inhibitors.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Review
Biochemistry & Molecular Biology
Ana Obaha, Marko Novinec
Summary: This comprehensive review explores the intricate regulation of peptidase activity in human health and disease, focusing on mechanisms such as exosites, allosteric sites, and zymogen activation. The review also discusses the influence of glycosaminoglycans and non-inhibitory binding proteins on enzyme activities.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Juliana Rey, Maike Breiden, Vanda Lux, Anika Bluemke, Maike Steindel, Kamilla Ripkens, Bastian Moellers, Kenny Bravo Rodriguez, Prisca Boisguerin, Rudolf Volkmer, Joel Mieres-Perez, Tim Clausen, Elsa Sanchez-Garcia, Michael Ehrmann
Summary: This study reports a novel and reversible mechanism of protease activation, where an inactive protease serves as the activator. This mechanism involves the formation of an allosteric complex between HTRA1 and calpain 2, and exhibits activity only towards specific conformations of substrates. These findings have important implications for understanding protein quality control and potential side effects of drug modulation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Chemistry, Multidisciplinary
Mojgan Asadi, Gabriel Oanca, Arieh Warshel
Summary: The study investigates the environmental effect on chemical catalysis of intramembrane protein cleavage, finding that the physical environment does not significantly affect the function of proteins and that conformational and substrate dynamics do not exhibit long-time coupling.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Plant Sciences
Anastasiya Lavell, Montgomery Smith, Yang Xu, John E. Froehlich, Cameron de la Mora, Christoph Benning
Summary: Rhomboid-like proteins play various regulatory roles in cells, and a study on Arabidopsis thaliana has identified a high-molecular-weight complex involving RBL10, ACP4, and CTI1, which are likely to affect chloroplast lipid metabolism. The findings offer insights into the mechanistic model of how interactions between these components impact lipid assembly, as well as refining the topology of RBL10 in the membrane. This study provides a stepping stone towards a deeper understanding of RBL10 function in Arabidopsis lipid metabolism.
Article
Biochemistry & Molecular Biology
Eyleen de Poel, Sacha Spelier, Ricardo Korporaal, Ka Wai Lai, Sylvia F. Boj, Katja Conrath, Cornelis K. van der Ent, Jeffrey M. Beekman
Summary: Combination therapy with CFTR modulators has shown to be more effective in treating CF, with ABBV/GLPG-2222/ABBV-2737/ABBV/GLPG-2451 combination demonstrating increased efficacy over VX-770/VX-809 for most organoids, despite variations in efficacy between different organoid cultures. Optimizing ABBV/GLPG-Triple therapy and characterizing efficacy in clinically relevant models remains important for CF treatment.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Lydia Koch, Birte Kespohl, Maria Agthe, Tim Schumertl, Stefan Dusterhoft, Marius K. Lemberg, Juliane Lokau, Christoph Garbers
Summary: Interleukin-11 (IL-11) activates target cells through different signaling pathways, including the shedding of IL-11R triggered by RHBDL2. RHBDL2 can cleave IL-11R within the cell, generating biologically active sIL-11R capable of trans-signaling IL-11 action.
Article
Biochemistry & Molecular Biology
Jule Truberg, Laura Hobohm, Alexander Jochimsen, Christine Desel, Michaela Schweizer, Matthias Voss
Summary: This study investigates the regulation and localization of Golgi enzymes by an intramembrane protease called SPPL3. The findings suggest that SPPL3 is predominantly located in the mid-Golgi and co-localizes with its substrates and non-substrate type II proteins. These results have important implications for understanding the role of SPPL3 in the regulation of Golgi glycosylation machinery.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2022)
Review
Cardiac & Cardiovascular Systems
Torben Mentrup, Florencia Cabrera-Cabrera, Bernd Schroeder
Summary: The LOX-1 receptor plays a crucial role in atherosclerosis, promoting oxLDL uptake and signaling cascade leading to foam cell formation. Proteolysis acts as a regulatory mechanism for LOX-1 function, generating cleavage products with different biological functions and potential diagnostic value.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2021)
Article
Microbiology
Sandra Olenic, Fiona Buchanan, Jordyn VanPortfliet, Daniel Parrell, Lee Kroos
Summary: Intramembrane metalloproteases play important roles in regulating biological processes by cleaving membrane-associated substrates. The study found that two conserved proline residues in the predicted short loop of SpoIVFB are crucial for the interaction and cleavage of Pro-sigma(K). The functions of other conserved residues in the short loop are not well understood.
JOURNAL OF BACTERIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Alexa L. Knight, Vinnie Widjaja, George P. Lisi
Summary: Mesophilic and thermophilic enzyme counterparts are studied to understand their functions under harsh conditions. Thermophiles regulate their structural ensemble through intra-protein communication and altered interactions with ligands to function well outside of standard temperature ranges. Recent studies have shown that the enhancement or diminution of allosteric crosstalk can be temperature-dependent and distinguish thermophilic enzymes from their mesophilic counterparts. However, the impact of temperature on allosteric function is understudied compared to other factors such as pH, mutations, or ligands.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Nina Kunova, Henrieta Havalova, Gabriela Ondrovicova, Barbora Stojkovicova, Jacob A. Bauer, Vladena Bauerova-Hlinkova, Vladimir Pevala, Eva Kutejova
Summary: Mitochondrial proteins are transported into mitochondria using a sophisticated system, and their proper folding and assembly rely on the cleavage of targeting presequences. Mitochondrial processing peptidases play a crucial role in mitochondrial homeostasis and their malfunctions are linked to severe human diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemical Research Methods
John D. Lapek, Zhenze Jiang, Jacob M. Wozniak, Elena Arutyunova, Steven C. Wang, M. Joanne Lemieux, David J. Gonzalez, Anthony J. O'Donoghue
MOLECULAR & CELLULAR PROTEOMICS
(2019)
Article
Biochemistry & Molecular Biology
Zhenlin Ouyang, Jan Felix, Jinhong Zhou, Yingmei Pei, Bohan Ma, Peter M. Hwang, M. Joanne Lemieux, Irina Gutsche, Fang Zheng, Yurong Wen
Review
Chemistry, Medicinal
Rui Chen, Aravindhan Ganesan, Isobel Okoye, Elena Arutyunova, Shokrollah Elahi, M. Joanne Lemieux, Khaled Barakat
MEDICINAL RESEARCH REVIEWS
(2020)
Article
Biophysics
John Paul Glaves, Joseph O. Primeau, Przemek A. Gorski, L. Michel Espinoza-Fonseca, M. Joanne Lemieux, Howard S. Young
BIOPHYSICAL JOURNAL
(2020)
Article
Multidisciplinary Sciences
Aravindhan Ganesan, Marawan Ahmed, Isobel Okoye, Elena Arutyunova, Dinesh Babu, William L. Turnbull, Joydeb Kumar Kundu, Justin Shields, Katharine Cheryl Agopsowicz, Lai Xu, Yasser Tabana, Nutan Srivastava, Guangzhi Zhang, Tae Chul Moon, Alexandr Belovodskiy, Mostofa Hena, Appan Srinivas Kandadai, Seyedeh N. Argess Hosseini, Mary Hitt, John Walker, Michael Smylie, Frederick G. West, Arno G. Siraki, M. Joanne Lemieux, Shokrollah Elahi, James A. Nieman, D. Lorne Tyrrell, Michael Houghton, Khaled Barakat
SCIENTIFIC REPORTS
(2019)
Review
Biochemistry & Molecular Biology
Laine Lysyk, Raelynn Brassard, Nicolas Touret, M. Joanne Lemieux
JOURNAL OF MOLECULAR BIOLOGY
(2020)
Article
Neurosciences
Wentong Long, Mohammad Fatehi, Shubham Soni, Rashmi Panigrahi, Koenraad Philippaert, Yi Yu, Rees Kelly, Brett Boonen, Amy Barr, Dominic Golec, Scott A. Campbell, Katarina Ondrusova, Matt Hubert, Troy Baldwin, M. Joanne Lemieux, Peter E. Light
JOURNAL OF PHYSIOLOGY-LONDON
(2020)
Article
Multidisciplinary Sciences
Wayne Vuong, Muhammad Bashir Khan, Conrad Fischer, Elena Arutyunova, Tess Lamer, Justin Shields, Holly A. Saffran, Ryan T. McKay, Marco J. van Belkum, Michael A. Joyce, Howard S. Young, D. Lorne Tyrrell, John C. Vederas, M. Joanne Lemieux
NATURE COMMUNICATIONS
(2020)
Editorial Material
Biochemistry & Molecular Biology
M. Joanne Lemieux, Michael Overduin
Summary: The field of membrane structural biology is rapidly evolving, with developments such as native nanodiscs and memteins changing the way we understand biological membranes. Tools like cryo-electron microscopy, X-ray crystallography, and nuclear magnetic resonance spectroscopy are advancing, but challenges remain in understanding how lipids and ligands interact at an atomic level.
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2021)
Article
Chemistry, Medicinal
Bing Bai, Alexandr Belovodskiy, Mostofa Hena, Appan Srinivas Kandadai, Michael A. Joyce, Holly A. Saffran, Justin A. Shields, Muhammad Bashir Khan, Elena Arutyunova, Jimmy Lu, Sardeev K. Bajwa, Darren Hockman, Conrad Fischer, Tess Lamer, Wayne Vuong, Marco J. van Belkum, Zhengxian Gu, Fusen Lin, Yanhua Du, Jia Xu, Mohammad Rahim, Howard S. Young, John C. Vederas, D. Lorne Tyrrell, M. Joanne Lemieux, James A. Nieman
Summary: This study describes novel antiviral compounds against coronaviruses, which have good activity and stability, and show effective inhibition of SARS-CoV-2 replication. They also exhibit better selectivity index and broad-spectrum antiviral activity against different types of coronaviruses.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Elena Arutyunova, Muhammad Bashir Khan, Conrad Fischer, Jimmy Lu, Tess Lamer, Wayne Vuong, Marco J. van Belkum, Ryan T. McKay, D. Lorne Tyrrell, John C. Vederas, Howard S. Young, M. Joanne Lemieux
Summary: The main protease of SARS-CoV-2 is a high priority drug target, and GC376 has been shown to effectively inhibit it. GC376 also demonstrates reversible binding and broad specificity, making it suitable for clinical trials. The stability and thermodynamic parameters of the protease were studied, revealing insights into the physical chemical properties of viral enzymes.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Biology
M'Lynn E. Fisher, Elisa Bovo, Rodrigo Aguayo-Ortiz, Ellen E. Cho, Marsha P. Pribadi, Michael P. Dalton, Nishadh Rathod, M. Joanne Lemieux, L. Michel Espinoza-Fonseca, Seth L. Robia, Aleksey Zima, Howard S. Young
Summary: DWORF has been identified as a direct activator of SERCA, increasing its turnover rate and promoting calcium reuptake in the absence of phospholamban. Fluorescence resonance energy transfer experiments revealed that DWORF has a higher affinity for SERCA in the presence of calcium.
Article
Chemistry, Medicinal
Wayne Vuong, Conrad Fischer, Muhammad Bashir Khan, Marco J. van Belkum, Tess Lamer, Kurtis D. Willoughby, Jimmy Lu, Elena Arutyunova, Michael A. Joyce, Holly A. Saffran, Justin A. Shields, Howard S. Young, James A. Nieman, D. Lorne Tyrrell, M. Joanne Lemieux, John C. Vederas
Summary: The study demonstrates that GC376 and its derivatives are effective inhibitors of Mpro in SARS-CoV-2, with improved affinity and therapeutic index. Crystallographic analysis reveals an alternative binding pocket in M-pro and the mechanism of alternative binding induced by polar groups or a nearby methyl. Additionally, new findings on solubility and colloidal formation in aqueous media are reported, along with the use of choline to increase solubility.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Laine Lysyk, Raelynn Brassard, Elena Arutyunova, Verena Siebert, Zhenze Jiang, Emmanuella Takyi, Melissa Morrison, Howard S. Young, Marius K. Lemberg, Anthony J. O'Donoghue, M. Joanne Lemieux
Summary: This study using recombinant PARL provides fundamental insights into its catalytic activity and substrate preferences, enhancing our understanding of its role in mitochondrial function.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Xiaocen Lu, Yurong Wen, Shuce Zhang, Wei Zhang, Yilun Chen, Yi Shen, M. Joanne Lemieux, Robert E. Campbell
Summary: The research team discovered and developed PhoCl2c and PhoCl2f, two variants with significant improvements in photocleavage rate, enabling more effective control of biomolecular activities in cells. The performance of these new variants was confirmed through X-ray crystal structures analysis and molecular dynamics simulations.