Review
Biochemistry & Molecular Biology
Jing-Liang Sun, Jin-Yu Li, Mei-Jing Wang, Ze-Ting Song, Jian-Xiang Liu
Summary: Protein homeostasis in plant organelles is crucial for cell functions during growth and stress responses; a balance between protein synthesis and degradation is required to maintain this stability. Various mechanisms have evolved in plants to ensure efficient import, correct folding, and maturation of proteins within organelles, influenced by developmental signals and environmental cues.
Article
Biochemistry & Molecular Biology
Amanda B. Abildgaard, Vasileios Voutsinos, Soren D. Petersen, Fia B. Larsen, Caroline Kampmeyer, Kristoffer E. Johansson, Amelie Stein, Tommer Ravid, Claes Andreasson, Michael K. Jensen, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen
Summary: Protein quality control (PQC) degrons are short protein segments that target misfolded proteins for proteasomal degradation, and chaperone-binding regions may function as PQC degrons. A canonical Hsp70-binding motif, the APPY peptide, functions as a dose-dependent PQC degron in yeast and human cells. The number of exposed Hsp70-binding sites in the yeast proteome correlates with reduced protein abundance and half-life.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Kristoffer E. Johansson, Bayan Mashahreh, Rasmus Hartmann-Petersen, Tommer Ravid, Kresten Lindorff-Larsen
Summary: Effective proteome homeostasis is crucial for cell and organism survival. Cells have efficient quality control systems to monitor and remove misfolded proteins. The nature and sequence properties of quality-control degrons are still unknown.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Carolyn Allain Breckel, Mark Hochstrasser
Summary: The proper folding of proteins is vital for their diverse functions, and misfolded proteins can potentially harm cells by forming aggregates. Protein quality control pathways are responsible for repairing or degrading abnormal proteins, with the ubiquitin-proteasome system being commonly employed.
Review
Biochemistry & Molecular Biology
Yunting Fu, Xifeng Li, Baofang Fan, Cheng Zhu, Zhixiang Chen
Summary: Maintaining functional protein homeostasis in chloroplasts is crucial for plant fitness and survival. Research has uncovered various mechanisms involved in chloroplast protein quality control and turnover, such as endosymbiotically-derived proteases, ubiquitin-dependent turnover, chloroplast-associated degradation, chloroplast unfolded protein response, and vesicle-mediated degradation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Long Fang, Ruofei Zhang, Lin Shi, Jiaying Xie, Long Ma, Yili Yang, Xiyun Yan, Kelong Fan
Summary: The study demonstrates the potential therapeutic effect of protein-nanocaged selenium as an epigenetic regulator against t(8;21) leukemia.
Article
Chemistry, Medicinal
Dipti Kanabar, Mimansa Goyal, Emma Kane, Tejashri Chavan, Abbas Kabir, Xuechun Wang, Snehal Shukla, Joseph Almasri, Sona Goswami, Gizem Osman, Marino Kokolis, Donald E. Spratt, Vivek Gupta, Aaron Muth
Summary: This study reports the structure-based design of small molecules that can bind to Gankyrin and inhibit its overexpression in breast and lung cancers, showing potential therapeutic value.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Kobe Janssen, Filip Claes, Dido Van de Velde, Vanessa L. Wehbi, Bert Houben, Yulia Lampi, Mieke Nys, Laleh Khodaparast, Ladan Khodaparast, Nikolaos Louros, Rob van der Kant, Joffre Verniers, Teresa Garcia, Meine Ramakers, Katerina Konstantoulea, Katerina Maragkou, Ramon Duran-Romana, Monica Musteanu, Mariano Barbacid, Bernard Scorneaux, Els Beirnaert, Joost Schymkowitz, Frederic Rousseau
Summary: Mutant KRAS is a challenging target for classical small molecule drugs, but this study shows that its misfolding can be induced by synthetic peptides derived from specific regions of the oncoprotein. These peptides were able to inhibit the function of mutant KRAS and showed antiproliferative activity against cancer cells. The findings provide proof-of-concept for exploiting the intrinsic misfolding propensity of KRAS as a therapeutic strategy.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Biochemistry & Molecular Biology
Anna M. Lenkiewicz, Magda Krakowczyk, Piotr Bragoszewski
Summary: The synthesis and targeting of mitochondrial proteins are essential processes for maintaining mitochondrial function and cell survival. The cytosolic protein homeostasis mechanism and the ubiquitin-proteasome system play critical roles in controlling the quality and supply of mitochondrial proteins. Mislocalization of mitochondrial proteins can contribute to disease development. Pathways involved in precursor maintenance and guidance in the cytosolic stages are crucial for restoring protein homeostasis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
Ka-Yiu Edwin Kong, Joao P. L. Coelho, Matthias J. Feige, Anton Khmelinskii
Summary: A healthy and functional proteome is crucial for cell physiology, but errors in protein metabolism and changes in the environment can disrupt proteome homeostasis. Mislocalized and orphan proteins can form due to targeting errors or improper assembly, impacting cellular functions. Quality control mechanisms play a role in minimizing the detrimental effects of these aberrant proteins, which are associated with aging and disease.
EXPERIMENTAL CELL RESEARCH
(2021)
Article
Neurosciences
Stacy L. Hrizo, Samantha L. Eicher, Tracey D. Myers, Ian McGrath, Andrew P. K. Wodrich, Hemanth Venkatesh, Daniel Manjooran, Sabrina Swoger, Kim Gagnon, Matthew Bruskin, Maria V. Lebedev, Sherry Zheng, Ana Vitantonio, Sungyoun Kim, Zachary J. Lamb, Andreas Vogt, Maura R. Z. Ruzhnikov, Michael J. Palladino
Summary: Triosephosphate isomerase (TPI) deficiency is a rare metabolic disorder characterized by reduced TPI protein stability and potential co-translational selection for polyubiquitination. A genome-wide RNAi screen targeting quality control proteins identified novel regulators of TPI(sugarkill) degradation, uncovering potential therapeutic pathways for TPI Df and other diseases.
NEUROBIOLOGY OF DISEASE
(2021)
Article
Genetics & Heredity
Christopher M. Hickey, Carolyn Breckel, Mengwen Zhang, William C. Theune, Mark Hochstrasser
Summary: Intracellular proteolysis through the ubiquitin-proteasome system regulates various processes in eukaryotes, with specific E3 ligases targeting proteins for degradation based on different signals. This study identified E3 ligases in yeast responsible for degrading proteins with different degradation signals, showing differential recognition of PQC substrates by the ubiquitin system in the cytoplasm and nucleus. Results in human cells confirmed these findings, indicating the ability of the ubiquitin system to target natural hydrophobic C-termini as degrons.
Article
Plant Sciences
Hong Du, Canqi Zheng, Muhmmad Aslam, Xihui Xie, Wanna Wang, Yingquan Yang, Xiaojuan Liu
Summary: The study revealed the responses of C. reinhardtii under high lead stress in physiological, genomic, transcriptomic, glycomic, and bioinformatic aspects, indicating that the endoplasmic reticulum-mediated pathways related to protein quality control were activated, potentially leading to the reduction of protein level.
FRONTIERS IN PLANT SCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Rebeca Ibarra, Heather R. Borror, Bryce Hart, Richard G. Gardner, Gary Kleiger
Summary: The yeast PQC ubiquitin ligase San1 contains multiple substrate binding sites along its polypeptide chain, showing specificity for unique misfolded proteins and enabling the formation of high affinity ubiquitin ligase-substrate complexes.
Review
Biochemistry & Molecular Biology
Yoshitaka Matsuo, Toshifumi Inada
Summary: Genetic mutations, mRNA processing errors, and lack of charged tRNAs can slow down or inhibit translating ribosomes. Monitoring systems are in place to detect and dispose of incomplete nascent chains and aberrant translation products to prevent accumulation and maintain protein homeostasis. Yeast models have been instrumental in uncovering the molecular mechanisms of these co-translational quality control systems.
Correction
Biochemistry & Molecular Biology
Chi Zhang, Simon R. Stockwell, May Elbanna, Robin Ketteler, Jamie Freeman, Bissan Al-Lazikani, Suzanne Eccles, Alexis De Haven Brandon, Florence Raynaud, Angela Hayes, Paul A. Clarke, Paul Workman, Sibylle Mittnacht
Article
Oncology
Charlotte K. Milton, Annette J. Self, Paul A. Clarke, Udai Banerji, Federica Piccioni, David E. Root, Steven R. Whittaker
MOLECULAR CANCER THERAPEUTICS
(2020)
Article
Multidisciplinary Sciences
Sheelagh Frame, Chiara Saladino, Craig MacKay, Butrus Atrash, Peter Sheldrake, Edward McDonald, Paul A. Clarke, Paul Workman, David Blake, Daniella Zheleva
Article
Biochemistry & Molecular Biology
Alexia Hervieu, Sara Farrah Heuss, Chi Zhang, Rachel Barrow-McGee, Carine Joffre, Ludovic Menard, Paul Andrew Clarke, Stephanie Kermorgant
Article
Medicine, Research & Experimental
Evon Poon, Tong Liang, Yann Jamin, Susanne Walz, Colin Kwok, Anne Hakkert, Karen Barker, Zuzanna Urban, Khin Thway, Rhamy Zeid, Albert Hallsworth, Gary Box, Marli E. Ebus, Marco P. Licciardello, Yordan Sbirkov, Glori Lazaro, Elizabeth Calton, Barbara M. Costa, Melanie Valenti, Alexis De Haven Brandon, Hannah Webber, Nicolas Tardif, Gilberto S. Almeida, Rossitza Christova, Gunther Boysen, Mark W. Richards, Giuseppe Barone, Anthony Ford, Richard Bayliss, Paul A. Clarke, Johann De Bono, Nathanael S. Gray, Julian Blagg, Simon P. Robinson, Suzanne A. Eccles, Daniella Zheleva, James E. Bradner, Jan Molenaar, Igor Vivanco, Martin Eilers, Paul Workman, Charles Y. Lin, Louis Chesler
JOURNAL OF CLINICAL INVESTIGATION
(2020)
Review
Biochemistry & Molecular Biology
Harvey E. Johnston, Rahul S. Samant
Summary: Protein misfolding plays a crucial role in ageing-related frailty and disease pathology. Understanding how to maintain protein homeostasis and how protein quality control systems fail with environmental stress and ageing remains an exciting area of research with potential implications for healthy ageing strategies.
Article
Multidisciplinary Sciences
Miranda P. Collier, Karen Betancourt Moreira, Kathy H. Li, Yu-Chan Chen, Daniel Itzhak, Rahul Samant, Alexander Leitner, Alma Burlingame, Judith Frydman
Summary: The study characterized recombinant human TRiC (hTRiC) using mass spectrometry techniques, revealing post-translational processing of its subunits. Interestingly, some subunits can promiscuously re-assemble into dimers with non-canonical contacts. CCT5 was found to be the most stable subunit and engaged in the greatest number of non-canonical dimer pairings.
SCIENTIFIC REPORTS
(2021)
Article
Chemistry, Analytical
Harvey E. Johnston, Kranthikumar Yadav, Joanna M. Kirkpatrick, George S. Biggs, David Oxley, Holger B. Kramer, Rahul S. Samant
Summary: Complete and reproducible extraction of protein is crucial for proteome analysis. Solvent precipitation SP3 (SP4) is proposed as an alternative method, which captures protein aggregates by centrifugation instead of magnetism. SP4 provides equivalent or higher protein yields and improved reproducibility. It also recovers more low-solubility and transmembrane proteins, offering higher recovery rates.
ANALYTICAL CHEMISTRY
(2022)
Meeting Abstract
Hematology
Sarah A. Bird, Amy Barber, Fernando J. Sialana, Marco P. Licciardello, Harvey Che, Habib Bouguenina, Yura Grabovska, Enze Liu, Yakinthi Chrisochoidou, Shannon Martin, Jyoti Choudhary, Brian A. Walker, Ian Collins, Paul Clarke, Charlotte Pawlyn
Article
Biochemical Research Methods
Rahul S. Samant, Silvia Batista, Mark Larance, Bugra Ozer, Christopher I. Milton, Isabell Bludau, Estelle Wu, Laura Biggins, Simon Andrews, Alexia Hervieu, Harvey E. Johnston, Bissan Al-Lazikhani, Angus I. Lamond, Paul A. Clarke, Paul Workman
Summary: The molecular chaperone HSP90 plays a role in stabilizing client proteins involved in oncogenesis and malignant progression. Inhibitors of HSP90 have diverse effects on the proteome, but previous studies have mainly focused on total protein levels rather than protein complex alterations. This study used SEC-MS to characterize early changes in native protein complexes after treatment with the HSP90 inhibitor tanespimycin in colon adenocarcinoma cells. The study identified novel HSP90 inhibitor-modulated proteins and provides a resource for further research in HSP90 pharmacology. The data is available via ProteomeXchange (identifier: PXD033459).
MOLECULAR & CELLULAR PROTEOMICS
(2023)
Article
Chemistry, Medicinal
A. Elisa Pasqua, Swee Y. Sharp, Nicola E. A. Chessum, Angela Hayes, Loredana Pellegrino, Michael J. Tucker, Asadh Miah, Birgit Wilding, Lindsay E. Evans, Carl S. Rye, N. Yi Mok, Manjuan Liu, Alan T. Henley, Sharon Gowan, Emmanuel De Billy, Robert te Poele, Marissa Powers, Suzanne A. Eccles, Paul A. Clarke, Florence I. Raynaud, Paul Workman, Keith Jones, Matthew D. Cheeseman
Summary: CCT251236, a potent chemical probe, was developed through a cell-based high-throughput screen to discover inhibitors of the transcription factor HSF1 that supports malignancy. The compound was optimized to mitigate P-glycoprotein efflux and eventually led to the design of a clinical candidate, CCT361814/NXP800 22, which demonstrated tumor regression in a human ovarian adenocarcinoma xenograft model. It has now progressed to phase 1 clinical trial as a potential treatment for refractory ovarian cancer and other malignancies.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Meeting Abstract
Geriatrics & Gerontology
Rahul Samant
INNOVATION IN AGING
(2022)
Meeting Abstract
Oncology
P. Workman, P. A. Clarke, R. Te Poele, M. Powers, G. Box, E. De Billy, A. De Haven Brandon, A. Hallsworth, A. Hayes, H. McCann, S. Sharp, M. Valenti, F. I. Raynaud, S. A. Eccles, M. Cheeseman, K. Jones
EUROPEAN JOURNAL OF CANCER
(2022)
Article
Biochemistry & Molecular Biology
Albert A. Antolin, Paul A. Clarke, Ian Collins, Paul Workman, Bissan Al-Lazikani
Summary: This study identified and systematically characterized the kinase cross-pharmacology of representative HSP90 inhibitors using computational and experimental methods, revealing unique off-target kinase pharmacology of certain clinical candidates. It was also shown that polypharmacology evolved during optimization to discover luminespib, with hit, leads, and clinical candidate having different profiles. The study recommends early computational and experimental characterization of polypharmacology in drug discovery projects to uncover new opportunities for multi-target drug design.
CELL CHEMICAL BIOLOGY
(2021)