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
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
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
Chemistry, Physical
Lipika Baidya, Govardhan Reddy
Summary: Aggregation of intrinsically disordered proteins (IDPs) is linked to neurodegenerative diseases. In this study, computer simulations were used to investigate the effect of acidic pH on the conformation of a specific protein. It was found that low pH induces compaction in the protein's dimensions, particularly in the region rich in glutamic acid residues, leading to increased β-sheet content. Conformations with high β-sheet content were observed to nucleate the aggregation process.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2022)
Review
Geriatrics & Gerontology
Jiajun Han, Yaohua Fan, Peipei Wu, Zifeng Huang, Xinrong Li, Lijun Zhao, Yichun Ji, Meiling Zhu
Summary: Parkinson's disease dementia is a common complication of Parkinson's disease that seriously affects patients' health and quality of life. The complex interplay of iron, alpha-synuclein, tau, beta-amyloid, and oxidative stress plays a pivotal role in the mechanism underlying PDD, leading to neuronal protein accumulation, neuroinflammation, and cell death. GSK3 beta is identified as a potential target for the prevention and treatment of PDD due to its central role in regulating the vicious cycle of molecular interactions.
FRONTIERS IN AGING NEUROSCIENCE
(2021)
Article
Multidisciplinary Sciences
Rebecca B. Berlow, H. Jane Dyson, Peter E. Wright
Summary: Intrinsically disordered proteins compete for binding to common regulatory targets to carry out their biological functions. The activation domains of HIF-1 alpha and CITED2 function as a unidirectional, allosteric molecular switch to control transcription of adaptive genes. The mechanistic details of this molecular switch were characterized through NMR spectroscopy and biophysical methods, revealing the contributions of individual binding motifs in CITED2. These findings provide insight into the complexity of molecular interactions involving disordered proteins and how they compete for occupancy of common targets.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Kevin A. Murray, Carolyn J. Hu, Sarah L. Griner, Hope Pan, Jeannette T. Bowler, Romany Abskharon, Gregory M. Rosenberg, Xinyi Cheng, Paul M. Seidler, David S. Eisenberg
Summary: Neurodegenerative diseases are characterized by the accumulation of aggregated proteins, and inhibiting the formation of these aggregates is a potential therapeutic strategy. Using de novo protein design, researchers have developed a library of mini-protein inhibitors that specifically target the amyloid structures of tau, Aβ, and α Syn. These inhibitors show promising results in preventing aggregation and rescuing motor deficits in animal models of PD and AD.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Taylor J. Fiolek, Katarina L. Keel, Jetze J. Tepe
Summary: The oligomerization of aggregation-prone intrinsically disordered proteins is associated with neurodegenerative diseases, and small molecule activators of the 20S proteasome subcomplex can restore proteasome activity and prevent protein accumulation. Compounds like fluspirilene show strong enhancement of 20S proteasome activity and have potential as therapeutic strategy for combating neurodegenerative diseases.
ACS CHEMICAL NEUROSCIENCE
(2021)
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
Biochemistry & Molecular Biology
Nahuel N. Foressi, Leandro Cruz Rodriguez, M. Soledad Celej
Summary: Tau and α-synuclein undergo liquid-liquid phase separation to form heterotypic droplets that exhibit increased resistance to electrostatic screening and are influenced by biologically relevant biomolecules. This phase separation process plays a significant role in the amyloid aggregation of Tau and α-synuclein.
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
(2023)
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, Multidisciplinary
Ushasi Pramanik, Atanu Nandy, Laxmikanta Khamari, Saptarshi Mukherjee
Summary: Intrinsically disordered proteins (IDPs) possess unique dynamic characteristics that are difficult to study using traditional methods. Single-molecule measurements provide a better understanding of the conformational transitions of IDPs. These approaches are important for revealing the structural transitions of IDPs and future research directions.
Review
Neurosciences
Urmi Sengupta, Rakez Kayed
Summary: This review summarizes the histopathological features of specific protein aggregation in several neurodegenerative diseases and discusses their overlap. It also highlights the synergistic interplay among Aβ, tau, and alpha-Syn in these diseases, suggesting a protein triumvirate.
PROGRESS IN NEUROBIOLOGY
(2022)
Article
Chemistry, Medicinal
Souvik Mondal, Krishna Prasad Ghanta, Sanjoy Bandyopadhyay
Summary: This study investigates the dynamic properties of water near the α-synuclein protein associated with Parkinson's disease. The results show that the translational and rotational mobility of water molecules near the peptide segments are significantly restricted, with water near the hydrophobic segment exhibiting more restricted diffusivity. The time scales of peptide-water and water-water hydrogen bond relaxations correlate with the diffusion of interfacial water molecules. The hindered dynamic environment near a specific segment can enhance early stages of peptide aggregation.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Multidisciplinary
Debapriya Das, Lisha Arora, Samrat Mukhopadhyay
Summary: Protein folding and dynamics are influenced by thermal and viscosity-mediated effects, with internal friction playing a crucial role. The study demonstrates that sequence-specific backbone dihedral barriers control local internal friction in proteins, with different amino acid sequences affecting the level of internal friction.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Physical
Priyanka Dogra, Shruti Arya, Avinash K. Singh, Anindya Datta, Samrat Mukhopadhyay
Summary: The conformational plasticity of intrinsically disordered proteins (IDPs) is important for their biological functions, and is governed by chain-chain and chain-solvent interactions. In this study, the conformational and solvation dynamics around the N and C-terminal segments of a protein called Pmel17, which forms functional amyloid responsible for melanin biosynthesis, were characterized using fluorescence measurements. The results showed slight compaction and slower rotational dynamics around the amyloidogenic C-terminal segment compared to the proline-rich N-terminal segment. This compaction was associated with restrained mobility of hydration water. These findings highlight the importance of sequence-dependent chain-solvent interactions in directing the conversion of dynamic IDPs into ordered amyloid assemblies.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Article
Chemistry, Multidisciplinary
Debapriya Das, Lisha Arora, Samrat Mukhopadhyay
Summary: Protein folding and dynamics are influenced by thermal and viscosity-mediated effects, with internal friction playing a crucial role. The study demonstrates that sequence-specific backbone dihedral barriers control local internal friction in proteins, with different amino acid sequences affecting the level of internal friction.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Sayanta Mahapatra, Anusha Sarbahi, Priyanka Madhu, Hema M. Swasthi, Abhishek Sharma, Priyanka Singh, Samrat Mukhopadhyay
Summary: This study investigates the role of substoichiometric Hsp104 in the formation and persistence of prefibrillar amyloid seeds. The results show that Hsp104 accelerates the formation of prefibrillar species and prolongs their persistence. In addition, Hsp104-modulated amyloid species have better seeding capability and exhibit distinct structural and dynamical characteristics compared to NM-only amyloids.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Instruments & Instrumentation
Kiran Ahlawat, Ramavtar Jangra, Shivam Chaturvedi, Chandra Prakash, Ambesh Dixit, Deepak Fulwani, Ankur Gupta, Neha Jain, Vibhor Tak, Ram Prakash
Summary: This paper presents a surface decontamination system that can replace traditional chemicals and scrubbing agents. The system utilizes UV-C light and metal oxide nano-catalysts to generate hydroxyl radicals, enhancing the deactivation process. It can work in shadow regions and has been optimized for disinfection efficiency. Tests have shown significant reduction in bacterial counts within just 2 minutes of exposure in the continuous operation of the system.
REVIEW OF SCIENTIFIC INSTRUMENTS
(2022)
Article
Multidisciplinary Sciences
Anamika Avni, Ashish Joshi, Anuja Walimbe, Swastik G. Pattanashetty, Samrat Mukhopadhyay
Summary: The authors introduced a unique single-droplet surface-enhanced Raman scattering (SERS) methodology to investigate molecular information within the mesoscopic liquid condensed phase. This study sheds light on the formation and regulation mechanism of biomolecular condensates. The highly sensitive measurements enable the capture of crucial interactions, conformational heterogeneity, and structural distributions.
NATURE COMMUNICATIONS
(2022)
News Item
Biophysics
Sandeep K. Rai, Samrat Mukhopadhyay
BIOPHYSICAL JOURNAL
(2022)
Review
Chemistry, Multidisciplinary
Debapriya Das, Samrat Mukhopadhyay
Summary: Protein folding and dynamics are influenced by both thermal and viscosity effects, including external viscous drag from solvent molecules and internal friction within the polypeptide chain. The physical origin of internal friction in intrinsically disordered proteins remains unclear, with diffusive conformational dynamics dominated by segmental motion of the backbone. Polymer models with internal friction are used to describe the friction in complex biopolymeric systems such as intrinsically disordered proteins.
ACCOUNTS OF CHEMICAL RESEARCH
(2022)
Editorial Material
Biochemistry & Molecular Biology
Samrat Mukhopadhyay
Summary: Intrinsically disordered proteins (IDPs) are a class of proteins that expand the functional repertoire and are associated with various biological functions and human diseases. This thematic issue provides current trends and contemporary views on the unique structural and dynamical characteristics of these proteins, as well as their misfolding behavior, aggregation behavior, and phase transitions into biomolecular condensates.
ESSAYS IN BIOCHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Sandeep K. Rai, Roopali Khanna, Anamika Avni, Samrat Mukhopadhyay
Summary: Biomolecular condensates formed through phase separation play crucial roles in cellular functions and disease. In this study, we investigate the complex coacervation of neuronal proteins tau and prion, driven by specific electrostatic interactions and characterized by dynamic liquid-like droplets. We employ a combination of time-resolved tools to reveal the formation of heterotypic condensates with domain-specific electrostatic nanoclusters. These condensates can be modulated by RNA, resulting in reversible, multiphasic ternary condensates of different morphologies. Aging leads to the conversion of droplets into solid-like co-assemblies, accompanied by the formation of amorphous and amyloid-like co-aggregates. Our findings provide mechanistic insights into the role of tau and PrP in neuropathology and highlight the broader biological significance of complex phase transitions.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Sayanta Mahapatra, Anusha Sarbahi, Neha Punia, Ashish Joshi, Anamika Avni, Anuja Walimbe, Samrat Mukhopadhyay
Summary: Prion-like self-perpetuating conformational conversion of proteins into amyloid aggregates is influenced by ATP molecules, which can both accelerate aggregation and disaggregate preformed fibrils. ATP modulates the formation and dissolution of amyloids and restricts autocatalytic amplification by controlling the amount of fragmentable and seeding-competent aggregates. Furthermore, ATP can promote phase separation-mediated aggregation of proteins harboring prion-like domains. These findings provide important mechanistic insights into the concentration-dependent chemical chaperoning by ATP against prion-like transmissions of amyloids.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Archit Gupta, Ashish Joshi, Kanika Arora, Samrat Mukhopadhyay, Purnananda Guptasarma
Summary: The bacterial chromosome, known as its nucleoid, is an amorphous assemblage of globular nucleoprotein domains that exist as an irregularly-shaped, membrane-less, intracellular compartment separated from the cell's cytoplasm. Two abundant nucleoid-associated proteins, HU and Dps, undergo spontaneous complex coacervation with different forms of DNA/RNA, causing condensation and compaction of nucleic acids into liquid-liquid phase separated condensates in vitro. These complex coacervation modes may serve as models for understanding the in vivo relationships among nucleoid-associated proteins, explaining the presence of multiple isoforms of HU and the roles of HU and Dps in E. coli growth.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Chemistry, Physical
Anamika Avni, Ashish Joshi, Samrat Mukhopadhyay
Summary: Vibrational Raman spectroscopy coupled with hydrogen/deuterium exchange can discern key structural features responsible for diverse amyloid polymorphs. This noninvasive and label-free method allows for the structural differentiation of distinct amyloid polymorphs, capturing conformational heterogeneity and structural distributions. This research provides insights into the molecular factors governing structural diversity in amyloid polymorphs and could potentially simplify the study of amyloid remodeling by small molecules.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Multidisciplinary
Antony Vincy, Yohan Gaikwad, Harshita Agarwal, Neha Jain, Raviraj Vankayala
Summary: In this study, a paper-based colorimetric dipstick sensor based on the principle of Prussian blue synthesis was developed for highly sensitive and rapid detection of bacterial contamination. The sensor is easy to fabricate and can detect bacteria up to 10(1) CFU/mL within minutes.
Article
Chemistry, Multidisciplinary
Rahul Kumar, Antony Vincy, Khushboo Rani, Neha Jain, Sarvar Singh, Ajay Agarwal, Raviraj Vankayala
Summary: This article presents an environmentally friendly method for the synthesis of highly luminescent carbon dots derived from camel milk, which can be used for sensing manganese ions and identifying potential anticancer activity against alpha-synuclein amyloids.
Article
Chemistry, Multidisciplinary
Rahul Kumar, Antony Vincy, Khushboo Rani, Neha Jain, Sarvar Singh, Ajay Agarwal, Raviraj Vankayala
Summary: In this study, highly luminescent carbon dots derived from camel milk were synthesized and used for sensing manganese ions and identifying their anticancer potential and antiamyloid activity. The carbon dots exhibited good water dispersibility, stable fluorescence, and excellent photostability, making them suitable for various biomedical applications.
Article
Biochemistry & Molecular Biology
Ankita Chadda, Alexander G. Kozlov, Binh Nguyen, Timothy M. Lohman, Eric A. Galburt
Summary: In this study, it was found that the DNA damage response in Mycobacterium tuberculosis differs from well-studied model bacteria. The DNA repair helicase UvrD1 in Mtb is activated through a redox-dependent process and is closely associated with the homo-dimeric Ku protein. Additionally, Ku protein is shown to stimulate the helicase activity of UvrD1.
JOURNAL OF MOLECULAR BIOLOGY
(2024)