Article
Biochemistry & Molecular Biology
Tobias Gruber, Marc Lewitzky, Lisa Machner, Ulrich Weininger, Stephan M. Feller, Jochen Balbach
Summary: Intrinsically disordered proteins (IDPs) lack tertiary structure elements and play important roles in cellular processes. This study focuses on the C-terminal region of Gab1, an IDP, and investigates its induced structure and binding properties under both non-crowding and crowding conditions. The results show that under crowding conditions, pre-structured motifs are formed in certain regions of Gab1, which are also the binding regions for the protein SHP2. Phosphorylation has no impact on the dynamics and disordered nature of Gab1. Therefore, biological crowders can enhance the binding capacity of SHP2 to Gab1, even in the absence of phosphorylation.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Samuel Naudi-Fabra, Martin Blackledge, Sigrid Milles
Summary: Single molecule fluorescence and nuclear magnetic resonance spectroscopy are powerful techniques for analyzing intrinsically disordered proteins. They provide complementary views to decipher the complex properties and interactions of IDPs, and have made significant contributions to our understanding of their molecular characteristics.
Article
Biochemistry & Molecular Biology
Olivia A. Fraser, Sophia M. Dewing, Emery T. Usher, Christy George, Scott A. Showalter
Summary: Intrinsically disordered proteins are frequently regulated through post-translational modification, but the mechanistic understanding of lysine N-epsilon-acetylation is lagging behind proteomic discoveries. Here, we present a non-perturbing NMR method to monitor N-epsilon-lysine acetylation, which allows detection without the need for exogenous tags. This method has broad applications in studying various systems including intrinsically disordered proteins and lysine deacetylase enzyme assays.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Yang Lu, Bhargy Sharma, Wei Long Soon, Xiangyan Shi, Tianyun Zhao, Yan Ting Lim, Radoslaw M. Sobota, Shawn Hoon, Giovanni Pilloni, Adam Usadi, Konstantin Pervushin, Ali Miserez
Summary: By combining transcriptomic and proteomic studies, this research obtained the complete primary sequences of slime proteins in velvet worms and identified key features for slime self-assembly. The study revealed that slime proteins contain cysteine residues that mediate the formation of multi-protein complexes via disulfide bonding. It also found that low complexity domains in the N-termini have a propensity for liquid-liquid phase separation. Moreover, the rigid and flexible domains of the slime proteins were mapped using solid-state nuclear magnetic resonance.
Article
Chemistry, Physical
Abani K. Bhuyan
Summary: Recent research has shown that the survival instincts of intrinsically disordered proteins (IDPs) are mainly based on their total charge, polar residue abundance, and lack of hydrophobic amino acids. This study used a plant IDP (AtPP16-1) to demonstrate that it exhibits negative thermal expansion (NTE) even when its tertiary structure is perturbed. Additionally, the study observed hydrodynamic shrinkage of the NTE IDP and found that the protein with denatured tertiary structure collapses to a dynamically rigid state. These findings may represent a generic property of IDPs.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Article
Immunology
Omar Naneh, Mirijam Kozorog, Franci Merzel, Robert Gilbert, Gregor Anderluh
Summary: Perforin is a crucial pore-forming protein in the immune system that clears virus-infected or tumor cells by delivering apoptosis-inducing granzymes. Its activity is regulated by calcium ions, and our study showed that binding of at least three calcium ions is required for stable perforin binding to the lipid membrane. We also found that mouse perforin has a higher affinity for calcium ions compared to human perforin, due to a specific residue difference.
FRONTIERS IN IMMUNOLOGY
(2023)
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
Chemistry, Physical
Souvik Dey, Matthew MacAinsh, Huan-Xiang Zhou
Summary: For intrinsically disordered proteins (IDPs), the dynamics of the backbone play a key role in encoding their function. The dynamics are regulated by local interactions, secondary structures, and glycines. These sequence-dependent changes in backbone dynamics allow IDPs to respond to binding partners in a versatile manner.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Review
Chemistry, Multidisciplinary
Aldo R. Camacho-Zarco, Vincent Schnapka, Serafima Guseva, Anton Abyzov, Wiktor Adamski, Sigrid Milles, Malene Ringkjobing Jensen, Lukas Zidek, Nicola Salvi, Martin Blackledge
Summary: This review introduces the applications of nuclear magnetic resonance (NMR) in understanding the structure, dynamic behavior, and interaction trajectories of intrinsically disordered proteins. NMR provides ensemble averaged structural and dynamic parameters for each assigned resonance, revealing the importance of these parameters in the kinetics and thermodynamics of cellular and extracellular reactions. Furthermore, NMR can uncover the mechanistic basis of functional disordered molecular assemblies that are crucial for human health.
Review
Chemistry, Multidisciplinary
Aldo R. Camacho-Zarco, Vincent Schnapka, Serafima Guseva, Anton Abyzov, Wiktor Adamski, Sigrid Milles, Malene Ringkjobing Jensen, Lukas Zidek, Nicola Salvi, Martin Blackledge
Summary: Intrinsically disordered proteins play essential roles in cellular and extracellular biochemistry. Nuclear magnetic resonance is a powerful tool for studying their structural and dynamic behavior, providing insights into reaction kinetics and thermodynamics essential for function. Recent applications of NMR have helped uncover the mechanistic basis of functional disordered molecular assemblies important for human health.
Article
Multidisciplinary Sciences
Vikas A. Tillu, James Rae, Ya Gao, Nicholas Ariotti, Matthias Floetenmeyer, Oleksiy Kovtun, Kerrie-Ann Mcmahon, Natasha Chaudhary, Robert G. Parton, Brett M. Collins
Summary: The study highlights the essential role of the three disordered domains of Cavin1 in caveola formation and dynamic trafficking, as well as the fuzzy electrostatic interactions between Cavin1 and caveolin-1 proteins, combined with membrane lipid interactions, in generating membrane curvature and maintaining a stable caveola coat.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Medicinal
Laszlo Petri, Peter Abranyi-Balogh, Darius Vagrys, Timea Imre, Nikolett Varro, Istvan Mandity, Anita Racz, Lucia Wittner, Kinga Toth, Estilla Zsofia Toth, Tunde Juhasz, Ben Davis, Gyoergy Miklos Keseru
Summary: In this study, a covalent design strategy targeting intrinsically disordered proteins (IDPs) was developed based on the promising results of targeted covalent inhibitors (TCIs) on challenging targets. Using tau protein as a model system, suitable warheads were introduced to non-covalent scaffolds of potential tau aggregation inhibitors. The designed covalent tau binders effectively inhibited tau aggregation in aggregation models, providing promising candidates for the treatment of tauopathies.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Sreemantee Sen, Harish Kumar, Jayant B. Udgaonkar
Summary: Tau protein fragment tau-K18 undergoes a disorder to order transition in the presence of lipid micelles and vesicles, forming helical structures induced by a phospholipid mimetic. It has been shown that the mechanism of helical structure formation involves an intermediate state I, which can further progress to form a final helical state with a time constant of 50-200 microseconds. The helical conformation is found to be an aggregation-competent state that can lead to the formation of amyloid fibrils.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Feng Yuan, Christopher T. Lee, Arjun Sangani, Justin R. Houser, Liping Wang, Eileen M. Lafer, Padmini Rangamani, Jeanne C. Stachowiak
Summary: Membrane curvature is crucial for cellular functions and recent studies have revealed the role of intrinsically disordered proteins in driving membrane bending. Repulsive interactions among disordered domains lead to convex curvature, while attractive interactions result in concave curvature, forming membrane-bound liquid-like condensates. This study investigates the effects of disordered domains containing both repulsive and attractive interactions on curvature. The findings show that the position of the attractive or repulsive domain relative to the membrane determines the curvature, with increasing ionic strength altering the transition from convex to concave. These results provide design rules for membrane bending by disordered proteins.
Review
Biochemistry & Molecular Biology
Lisa Marie Ramirez, Markus Zweckstetter
Summary: Proteostasis is maintained by a network of molecular chaperones, with Hsp90 being a prominent member. While the chaperone function of Hsp90 has been extensively studied, its interaction with intrinsically disordered proteins (IDPs) remains poorly understood. This review highlights recent advances in understanding the mechanisms of Hsp90-mediated chaperoning of IDPs, focusing on tau and α-synuclein, and provides insights into the modulation of chaperone-client interaction in neurodegenerative diseases.
CURRENT OPINION IN CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Sarah J. Martin, I-Jen Chen, A. W. Edith Chan, Nicolas Foloppe
BIOORGANIC & MEDICINAL CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
Christopher A. Waudby, Margaux Ouvry, Ben Davis, John Christodoulou
JOURNAL OF BIOMOLECULAR NMR
(2020)
Article
Chemistry, Multidisciplinary
Thomas D. Downes, S. Paul Jones, Hanna F. Klein, Mary C. Wheldon, Masakazu Atobe, Paul S. Bond, James D. Firth, Ngai S. Chan, Laura Waddelove, Roderick E. Hubbard, David C. Blakemore, Claudia De Fusco, Stephen D. Roughley, Lewis R. Vidler, Maria Ann Whatton, Alison J. -A. Woolford, Gail L. Wrigley, Peter O'Brien
CHEMISTRY-A EUROPEAN JOURNAL
(2020)
Article
Chemistry, Multidisciplinary
Lisa M. Baker, Anthony Aimon, James B. Murray, Allan E. Surgenor, Natalia Matassova, Stephen D. Roughley, Patrick M. Collins, Tobias Krojer, Frank von Delft, Roderick E. Hubbard
COMMUNICATIONS CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
Eleni Makraki, John F. Darby, Marta G. Carneiro, James D. Firth, Alex Heyam, A. B. Eiso, Peter O'Brien, Gregg Siegal, Roderick E. Hubbard
BIOCHEMICAL JOURNAL
(2020)
Article
Chemistry, Medicinal
Douglas S. Williamson, Garrick P. Smith, Gitte K. Mikkelsen, Thomas Jensen, Pamela Acheson-Dossang, Lassina Badolo, Simon T. Bedford, Victoria Chell, I-Jen Chen, Pawel Dokurno, Morten Hentzer, Samantha Newland, Stuart C. Ray, Terry Shaw, Allan E. Surgenor, Lindsey Terry, Yikang Wang, Kenneth Christensen
Summary: In this study, inhibitors of LRRK2 and mutants were optimized based on the X-ray structures of LRRK2 kinase domain surrogates. The resulting compounds showed increased potency and selectivity for LRRK2, making them useful as chemical probes for studying LRRK2 inhibition in Parkinson's disease treatment.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Laszlo Petri, Peter Abranyi-Balogh, Darius Vagrys, Timea Imre, Nikolett Varro, Istvan Mandity, Anita Racz, Lucia Wittner, Kinga Toth, Estilla Zsofia Toth, Tunde Juhasz, Ben Davis, Gyoergy Miklos Keseru
Summary: In this study, a covalent design strategy targeting intrinsically disordered proteins (IDPs) was developed based on the promising results of targeted covalent inhibitors (TCIs) on challenging targets. Using tau protein as a model system, suitable warheads were introduced to non-covalent scaffolds of potential tau aggregation inhibitors. The designed covalent tau binders effectively inhibited tau aggregation in aggregation models, providing promising candidates for the treatment of tauopathies.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Stephanie Wills, Ruben Sanchez-Garcia, Tim Dudgeon, Stephen D. Roughley, Andy Merritt, Roderick E. Hubbard, James Davidson, Frank von Delft, Charlotte M. Deane
Summary: Fragment merging is a promising approach to advancing fragments directly to on-scale potency. Searching commercial catalogues allows for quick and cost-effective identification of these merges, circumventing the challenge of synthetic accessibility.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
S. Paul Jones, James D. Firth, Mary C. Wheldon, Masakazu Atobe, Roderick E. Hubbard, David C. Blakemore, Claudia De Fusco, Simon C. C. Lucas, Stephen D. Roughley, Lewis R. Vidler, Maria Ann Whatton, Alison J-A Woolford, Gail L. Wrigley, Peter O'Brien
Summary: This study reports the synthesis of piperidine-based 3D fragment building blocks and demonstrates their suitability for fragment-based drug discovery programs.
RSC MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Zoltan Szlavik, Marton Csekei, Attila Paczal, Zoltan B. Szabo, Szabolcs Sipos, Gabor Radics, Agnes Proszenyak, Balazs Balint, James Murray, James Davidson, Ijen Chen, Pawel Dokurno, Allan E. Surgenor, Zoe Marie Daniels, Roderick E. Hubbard, Gaetane Le Toumelin-Braizat, Audrey Claperon, Gaelle Lysiak-Auvity, Anne-Marie Girard, Alain Bruno, Maia Chanrion, Frederic Colland, Ana-Leticia Maragno, Didier Demarles, Olivier Geneste, Andras Kotschy
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
Felix Torres, Dhiman Ghosh, Dean Strotz, Celestine N. Chi, Ben Davis, Julien Orts
RSC MEDICINAL CHEMISTRY
(2020)