Article
Multidisciplinary Sciences
Ayaka Tomihari, Mako Kiyota, Akira Matsuura, Eisuke Itakura
Summary: Proteostasis is crucial for stress resistance and aging. In this study, the degradation pathway of alpha 2-macroglobulin (alpha M-2) was identified, showing its role in lysosomal degradation of extracellular misfolded proteins. Comparative analysis with clusterin revealed that alpha M-2 selectively targets aggregation-prone proteins. These findings shed light on the understanding of protein degradation pathways for extracellular proteins.
SCIENTIFIC REPORTS
(2023)
Article
Multidisciplinary Sciences
Soraia R. Mendes, F. Xavier Gomis-Rueth, Theodoros Goulas
Summary: Human alpha(2)-macroglobulin (h alpha M-2) is a large homotetrameric protein involved in the broad inhibition of endopeptidases. After cleavage, h alpha M-2 undergoes conformational changes and eventually entraps the peptidase through a Venus flytrap mechanism. Biochemical and biophysical characterization of purified h alpha M-2 from fresh or frozen plasma showed no differences in molecular or functional properties, indicating that native h alpha M-2 remains functional despite freezing.
SCIENTIFIC REPORTS
(2023)
Review
Hematology
Jeremy Lagrange, Thomas Lecompte, Tanja Knopp, Patrick Lacolley, Veronique Regnault
Summary: A2M is an antiproteinase that plays an inhibitory role by trapping proteinases with its unique cage structure. Its synthesis increases in inflammatory diseases and it can trap various proteinases involved in coagulation and fibrinolysis. Therefore, A2M plays an important role in the balanced regulation of hemostasis.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2022)
Review
Immunology
Jennifer Vandooren, Yoshifumi Itoh
Summary: Alpha-2-macroglobulin is known for its role as a broad-spectrum protease inhibitor and has additional functions such as regulating proteolysis, promoting cell migration, and binding cytokines, especially crucial in immune-cell function. This review provides an overview of all functions of Alpha-2-macroglobulin in the context of inflammation, immunity, and infections.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Milos Sunderic, Tamara Vasovic, Milos Milcic, Cedo Miljevic, Olgica Nedic, Milan R. Nikolic, Nikola Gligorijevic
Summary: The study revealed moderate binding affinity between alpha M-2 and clozapine, without significant conformational changes in the protein. Both substances were found to shield each other from the deleterious influence of strong oxidants, suggesting a potential synergistic protective effect against neural tissue injury caused by disturbed proteostasis or oxidative stress.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Article
Immunology
Naseba Naseraldeen, Regina Michelis, Masad Barhoum, Judith Chezar, Tamar Tadmor, Ariel Aviv, Lev Shvidel, Adi Litmanovich, Mona Shehadeh, Galia Stemer, Ety Shaoul, Andrei Braester
Summary: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the western world. Immunotherapy is one of the treatments offered for CLL, which activates the complement system through the formation of IgG-hexamers. The presence of higher levels of IgG-aggregates in CLL patients and their ability to activate the complement system more efficiently than in normal controls suggest potential for improving current immunotherapy regimens.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Veterinary Sciences
Hyun-Eui Park, Jin-Sik Park, Hong-Tae Park, Jeong-Gyu Choi, Jeong-Ih Shin, Myunghwan Jung, Hyung-Lyun Kang, Seung-Chul Baik, Woo-Kon Lee, Donghyuk Kim, Han Sang Yoo, Min-Kyoung Shin
Summary: Johne's disease, caused by Mycobacterium avium subsp. paratuberculosis, leads to chronic granulomatous enteritis in ruminants, resulting in economic losses in the dairy industry. A2M has shown potential as a diagnostic biomarker for MAP infection with high sensitivity and specificity, offering improved detection rates for subclinical shedders and MAP-exposed animals.
FRONTIERS IN VETERINARY SCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Kristine Donahue, Haibo Xie, Miyang Li, Ang Gao, Min Ma, Yidan Wang, Rose Tipton, Nicole Semanik, Tina Primeau, Shunqiang Li, Lingjun Li, Weiping Tang, Wei Xu
Summary: Researchers have identified a compound called dip G as a potential HSP90 modulator that can promote the degradation of ER, a major oncogenic protein in breast cancer, without being affected by ER LBD mutations that drive endocrine resistance.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Milos Sunderic, Nikola Gligorijevic, Milos Milcic, Simeon Minic, Olgica Nedic, Milan Nikolic
Summary: This study investigates the interaction between nutraceutical phycocyanobilin (PCB) and the universal anti-protease protein human alpha-2-macroglobulin (alpha M-2) under simulated physiological conditions. The results show that PCB binds to alpha M-2 at two high energy binding sites, leading to moderate affinity between the two molecules. The binding of PCB also protects alpha M-2 from oxidation and preserves its anti-protease activity.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Biochemistry & Molecular Biology
Samira Zouhir, Carlos Contreras-Martel, Daniel Maragno Trindade, Ina Attree, Andrea Dessen, Pauline Macheboeuf
Summary: The study found that in Pseudomonas aeruginosa, MagC may act as a link between MagD macroglobulin and peptidoglycan, providing stability and regulation for the entire complex.
Article
Fisheries
Yongli Wu, Yali Liu, Huixian Zhang, Xin Wang, Qiang Lin
Summary: Seahorses, being ovoviviparous fish, have a unique immune system where alpha-2 macroglobulin (alpha 2M) plays a significant role in paternal immunoprotection during male pregnancy. The study revealed that alpha 2M gene in seahorses has a broad expression pattern, with the highest expression in the liver and brood pouch. After challenge experiments, alpha 2M expression in the inner pseudoplacenta of the brood pouch was upregulated along with important immune factors, indicating its crucial role in immunoprotection and immune response regulation during male pregnancy in seahorses.
Article
Biology
Xiaoxing Huang, Youwang Wang, Cong Yu, Hui Zhang, Qiang Ru, Xinxin Li, Kai Song, Min Zhou, Ping Zhu
Summary: This study reports the structures of human alpha-2-macroglobulin and reveals its dynamic transformation as a protease inhibitor and the molecular mechanism of substrate entrapment.
SCIENCE CHINA-LIFE SCIENCES
(2022)
Article
Oncology
Jisu Lee, Hyun Sik Park, Seung Ro Han, Yun Hee Kang, Ji Young Mun, Dong Wook Shin, Hyun-Woo Oh, Yoon-Kyoung Cho, Myung-Shin Lee, Jinsung Park
Summary: Extracellular vesicles derived from urine, specifically urinary EVs (uEVs), have shown promise as diagnostic biomarkers for urogenital cancers. This study identified uEV-derived alpha-2-macroglobulin (a2M) as a novel diagnostic biomarker for bladder cancer (BC) and validated its upregulation in patient uEVs. The use of the centrifugal microfluidic tangential flow filtration device ExoDisc was found to be more effective for uEV protein analysis compared to classical differential centrifugation. These findings suggest that this approach for EV analysis can lead to the identification of clinically meaningful uEV-based biomarkers for cancer diagnosis.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Aleksandr Viktorovich Protasov, Olga Alexandrovna Mirgorodskaya, Yuri Petrovich Kozmin, Johan Gobom
Summary: In this study, we found that amyloid beta (A beta) peptides inhibit their binding with alpha-2-macroglobulin, affecting the ability of trypsin to cleave alpha 2M 705-715. Complete inhibition requires two A beta peptide molecules attached to one alpha 2M molecule, and proteolytic cleavage and oxidation also affect the inhibitory action of A beta peptides.
Article
Chemistry, Analytical
Pelin Yildiz, Sureyya Ozcan
Summary: Recent advances in proteomics technologies have allowed for high-throughput analysis of thousands of proteins. In this study, the correlation between protein concentration and corresponding unique peptide responses was investigated under conventional proteolytic digestion conditions. The results indicate that reproducible peptide signals could be misleading in clinical studies and that peptide selection could significantly impact the protein level outcome. This study is the first to explore quantitative protein-peptide correlations in biological samples using all unique peptides representing the same protein, and it opens up a discussion on peptide-based proteomics.
Review
Biochemistry & Molecular Biology
M. Elizabeth Fini, Shinwu Jeong, Mark R. Wilson
Summary: Evidence supports the potential of the glycoprotein CLU as a novel therapeutic for dry eye, protecting and repairing the ocular surface while dampening the autoimmune response. Future work will focus on human clinical trials to further investigate the therapeutic promise of CLU.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Sandeep Satapathy, Mark R. Wilson
Summary: Clusterin (CLU) is the first reported secreted mammalian chaperone that impacts serious diseases associated with inappropriate extracellular protein aggregation. Studies have shown that stress-induced release of CLU into the cytosol facilitates the trafficking of misfolded proteins for degradation, suggesting its critical role in intracellular and extracellular proteostasis. Further research is needed to establish CLU as a unique chaperone performing synergic roles in maintaining protein homeostasis.
TRENDS IN BIOCHEMICAL SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Sandeep Satapathy, Mark R. Wilson
Summary: Proteostasis refers to the delicate balance between protein synthesis, folding, localization, and degradation inside and outside cells. Our understanding of extracellular proteostasis is limited to 11 established extracellular chaperones (ECs). These multifunctional proteins work together to restore homeostasis at sites of tissue damage, infection, and inflammation, raising questions for future research.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2022)
Review
Ophthalmology
Mark R. Wilson, Sandeep Satapathy, Shinwu Jeong, M. Elizabeth Fini
Summary: This article highlights the importance of proteostasis and the role of the extracellular chaperone protein clusterin in eye diseases. Clusterin binds to and inhibits the aggregation of misfolded proteins, contributing to proteostasis, cytoprotection, and anti-inflammatory processes. Further research is needed to fully understand clusterin's involvement in diseases involving protein deposits and explore its potential therapeutic use.
PROGRESS IN RETINAL AND EYE RESEARCH
(2022)
Article
Cell Biology
Jordan H. Cater, Noralyn B. Manucat-Tan, Demi K. Georgiou, Guomao Zhao, Irina A. Buhimschi, Amy R. Wyatt, Marie Ranson
Summary: This study reveals the role of PAI-2 in controlling fibrinolysis and protein aggregation in diseases like Alzheimer's and preeclampsia.
Article
Biochemistry & Molecular Biology
Rosie Bell, Rebecca J. Thrush, Marta Castellana-Cruz, Marc Oeller, Roxine Staats, Aishwarya Nene, Patrick Flagmeier, Catherine K. Xu, Sandeep Satapathy, Celine Galvagnion, Mark R. Wilson, Christopher M. Dobson, Janet R. Kumita, Michele Vendruscolo
Summary: The N-terminal acetylation of alpha-synuclein alters its aggregation behavior, reducing its rate of aggregation and affecting the structural properties of its fibrillar aggregates.
Article
Cell Biology
Abigail K. Elias, Mark R. Wilson, John A. Carver, Ian F. Musgrave
Summary: Clusterin plays an important role in preventing the formation of SEVI amyloid fibrils, dissociating them, and mitigating their enhancement of HIV infection in semen.
Article
Biochemistry & Molecular Biology
Shravan K. Chintala, Jinhong Pan, Sandeep Satapathy, Rebecca Condruti, Zixuan Hao, Pei-wen Liu, Christian F. O'Conner, Joseph T. Barr, Mark R. Wilson, Shinwu Jeong, M. Elizabeth Fini
Summary: There is a high demand for therapeutics to treat ocular surface barrier damage caused by dry eye and related diseases. CLU, a natural tear glycoprotein, has shown the ability to seal and heal epitheliopathy in mice models of dry eye. In this study, CLU was found to effectively seal the damaged ocular surface barrier induced by an ophthalmic preservative, while other proteins in tears, such as TIMP1 and LCN1, showed no sealing activity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Cell Biology
Sandeep Satapathy, Mark R. Wilson
Summary: Protein quality control is critical for stem cell differentiation during regeneration. The functions of extracellular chaperones in neuronal injury and disease are not well understood. This review highlights the potential of investigating the effects of extracellular chaperones on neuronal repair and regeneration for developing new therapies.
NEURAL REGENERATION RESEARCH
(2023)
Review
Cell Biology
Nicholas J. J. Geraghty, Sandeep Satapathy, Mark R. R. Wilson
Summary: The immune system is crucial for organism protection. Complement and ECs play important roles in maintaining protein homeostasis and controlling immune processes. They may interact with pathogens and immune responses, and influence the development of various diseases.
Article
Critical Care Medicine
Jean-Francois Augusto, Celine Beauvillain, Caroline Poli, Lea Paolini, Isabelle Tournier, Pascale Pignon, Simon Blanchard, Laurence Preisser, Raffaella Soleti, Chloe Delepine, Marine Monnier, Isabelle Douchet, Pierre Asfar, Francois Beloncle, Olivier Guisset, Renaud Prevel, Alain Mercat, Emeline Vinatier, Julien Goret, Jean-Francois Subra, Dominique Couez, Mark R. Wilson, Patrick Blanco, Pascale Jeannin, Yves Delneste
Summary: Extracellular histones released during extensive cell death can promote inflammation and cell death, and clusterin (CLU) can reduce their deleterious properties. Decreased levels of CLU were observed in patients with sepsis, and CLU deficiency was associated with increased mortality in mouse models of sepsis. CLU supplementation improved mouse survival in a sepsis model.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(2023)
Review
Clinical Neurology
Mark R. Wilson, Sandeep Satapathy, Michele Vendruscolo
Summary: The proteostasis system regulates cellular processes of protein synthesis, folding, concentration, trafficking, and degradation. The mechanisms of extracellular proteostasis, particularly in the context of neurodegenerative diseases, are not well understood, but growing evidence suggests that impairment of this system may contribute to neuronal death.
NATURE REVIEWS NEUROLOGY
(2023)
Editorial Material
Oncology
Mark R. Wilson, Sandeep Satapathy, Michele Vendruscolo
CLINICAL AND TRANSLATIONAL MEDICINE
(2023)
Article
Chemistry, Multidisciplinary
Manjeet Kumar, Cristina Cantarutti, David C. C. Thorn, Vittorio Bellotti, Gennaro Esposito, Mark R. R. Wilson, Heath Ecroyd, John A. A. Carver
Summary: This study investigated the fibril formation of a variant of ss 2-microglobulin and the role of clusterin in regulating this process. The presence of charged amino acids affected the fibril formation, indicating the involvement of electrostatic interactions. Clusterin interacted with the monomeric, prefibrillar and fibrillar forms of the variant through hydrophobic and electrostatic forces. It stabilized the fibrils and inhibited nucleation, potentially preventing amyloid proliferation and deposition in tissues.
AUSTRALIAN JOURNAL OF CHEMISTRY
(2023)
Article
Cell Biology
Sandeep Satapathy, Holly Walker, James Brown, Yann Gambin, Mark R. Wilson
Summary: This study reveals that cell stress induces the release of clusterin (CLU), a usually secreted chaperone, into the cytosol. CLU can interact with cytosolic misfolded proteins, directing them to degradation through autophagy and the proteasome, and protect cells from stress.
