Review
Biochemistry & Molecular Biology
Emma Langella, Martina Buonanno, Giuseppina De Simone, Simona Maria Monti
Summary: hCA IX is a tumor-associated enzyme that is over-expressed in many tumors. This article aims to provide an overview of the poorly investigated proteoglycan-like domain of hCA IX and its role in modulating catalytic activity, tumor spreading, and migration. Special attention is given to the newly discovered disordered features of the PG domain and its potential diagnostic and therapeutic applications.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Biophysics
Derya Vural, Utsab R. Shrestha, Loukas Petridis, Jeremy C. Smith
Summary: The local structure of water molecules hydrating a globular protein and an intrinsically disordered protein (IDP) was compared using molecular dynamics simulation. The results showed that both proteins experienced perturbations in the first hydration shell, but the perturbation was more significant for the folded protein. This difference was attributed to an increase in the fraction of hydration water molecules interacting with oxygen in the IDP's first hydration shell.
BIOPHYSICAL JOURNAL
(2023)
Article
Chemistry, Physical
Zhengsong Pan, Junxi Mu, Hai-Feng Chen
Summary: Intrinsically disordered proteins (IDPs) play critical roles in biological processes, but sampling their conformational information is challenging. Molecular dynamics (MD) simulations have become the primary tool, but the accuracy depends on force field and water model. A new three-point water model named OPC3-B has been developed for IDPs, which outperforms other water models in terms of accuracy and transferability. This water model can provide insights into the research of sequence-disordered-function paradigm for IDPs.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
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)
Review
Biochemistry & Molecular Biology
Rachel Evans, Sravani Ramisetty, Prakash Kulkarni, Keith Weninger
Summary: Intense study of intrinsically disordered proteins (IDPs) began in the late 1990s and revealed their important functions. Over the past two decades, it has become clear that IDPs play critical roles in various biological phenomena. The application of integrative structural biology has emerged as an essential approach to understanding IDP phenomena.
Article
Chemistry, Physical
Jared M. Lalmansingh, Alex T. Keeley, Kiersten M. Ruff, Rohit V. Pappu, Alex S. Holehouse
Summary: Conformational heterogeneity is a characteristic feature of intrinsically disordered proteins and protein regions. Simulations based on atomistic and coarse-grained models are commonly used to understand the sequence-specific interactions and functions of these proteins. In this study, a new analysis toolkit called SOURSOP is introduced, which provides a collection of easy-to-use functions to characterize the conformational ensembles of intrinsically disordered proteins.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
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
Cell Biology
Alex S. Holehouse, Birthe B. Kragelund
Summary: Intrinsically disordered protein regions, lacking a stable 3D structure, are structurally heterogeneous and widely present in all kingdoms of life. Despite their lack of a defined structure, these regions play essential roles in cellular processes and can be regulated by their structural and chemical context. Recent studies have advanced our understanding of the link between protein sequence and conformational behavior in disordered regions, but the connection between sequence and molecular function is still not well defined.
NATURE REVIEWS MOLECULAR CELL BIOLOGY
(2023)
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, Multidisciplinary
Lukas S. Stelzl, Lisa M. Pietrek, Andrea Holla, Javier Oroz, Mateusz Sikora, Juergen Koefinger, Benjamin Schuler, Markus Zweckstetter, Gerhard Hummer
Summary: This study builds a structural ensemble of the tau K18 protein and reveals the factors controlling the balance between functional and disease-associated conformational states. It shows that pathogenic mutations shift the population from functional to aggregation-prone conformations. This research provides a detailed view of the equilibrium between functional and aggregation-prone states of the tau K18 protein.
Article
Chemistry, Multidisciplinary
Anton Abyzov, Eckhard Mandelkow, Markus Zweckstetter, Nasrollah Rezaei-Ghaleh
Summary: The dynamics of a 441-residue long intrinsically disordered protein (IDP), tau protein, were investigated in the temperature range of 0-25 degrees C. The results suggest that at higher temperatures, the fast backbone conformational fluctuations and slower chain segmental motions of the protein might become inseparable. This study demonstrates the remarkable dynamic plasticity of this prototypical IDP and highlights the need for dynamic studies of IDPs at multiple temperatures.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Biology
Aayush Gupta, Souvik Dey, Alan Hicks, Huan-Xiang Zhou
Summary: This study developed generative autoencoders that can learn from short molecular dynamics simulations and generate full conformational ensembles of intrinsically disordered proteins.
COMMUNICATIONS BIOLOGY
(2022)
Article
Chemistry, Medicinal
Nitin Kumar Singh, Pratyasha Bhardwaj, Mithun Radhakrishna
Summary: Predicting disordered regions in proteins is important for understanding their functions, dynamics, and interactions. The algorithm HydroDisPred (HDP) accurately predicts these regions using the fraction of hydrophobicity in each protein segment. HDP has been validated and found to be as effective as, if not better than, existing algorithms. It is a simple and effective method for identifying disordered regions in proteins and is not affected by the availability of training data.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Review
Biochemistry & Molecular Biology
Rakesh Trivedi, Hampapathalu Adimurthy Nagarajaram
Summary: This review discusses different aspects of disordered proteins and protein regions, as well as the experimental and computational methods used to characterize them. Additionally, the role of disordered proteins in diseases and their potential as drug targets are explored.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
J. Schilz, U. Binder, L. Friedrich, M. Gebauer, C. Lutz, M. Schlapschy, A. Schiefner, A. Skerra
Summary: Pro/Ala-rich sequences (PAS) are developed as a biological alternative to PEG for generating biopharmaceuticals with extended plasma half-life. Monoclonal antibodies against different PAS versions were successfully generated in this study, with key interactions involving hydrogen bonds and Van der Waals contacts. Ala emerged as a crucial feature for epitope recognition in anti-PAS complexes.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Review
Cell Biology
Shwetha Nanjundaiah, Hariharakrishnan Chidambaram, Madhura Chandrashekar, Subashchandrabose Chinnathambi
Summary: Cholesterol, a crucial component of the cell membrane, plays a significant role in the brain by influencing synaptic transmission, neuronal signaling, and neurodegenerative diseases. Dysregulation of cholesterol trafficking is linked to increased production of hyperphosphorylated Tau and Amyloid-beta protein, leading to Alzheimer's disease. Understanding the regulation of cholesterol metabolism and Tau phosphorylation is essential for managing the pathogenesis of Alzheimer's disease.
CELLULAR AND MOLECULAR NEUROBIOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Petr Konarev, Andrey Yu Gruzinov, Haydyn D. T. Mertens, Dmitri Svergun
Summary: The article presents a general approach for calculating and analyzing SAXS data from lipid mixtures, allowing for the restoration of electron density of lipid bilayers and size distribution of vesicles over the entire angle range. The method is implemented in a computer program, LIPMIX, and demonstrated on layered lipid vesicles undergoing extrusion. This approach is expected to be useful for analyzing various types of lipid-based systems and interactions between target drug molecules and carrier/delivery systems.
JOURNAL OF APPLIED CRYSTALLOGRAPHY
(2021)
Editorial Material
Biochemical Research Methods
Petr V. Konarev, Dmitri I. Svergun
Article
Biochemistry & Molecular Biology
Petr Konarev, Melissa A. Graewert, Cy M. Jeffries, Masakazu Fukuda, Taisiia A. Cheremnykh, Vladimir V. Volkov, Dmitri Svergun
Summary: SAXS is commonly used for structural analysis of biological macromolecules in solution, and combining SAXS with chromatography setups has become popular in research. The computer program EFAMIX, based on evolving factor analysis (EFA), efficiently restores scattering and concentration profiles of components from mixed SAXS data, proving useful for interpretation and analysis of fractions in the sample.
Biographical-Item
Chemistry, Multidisciplinary
Dmitri Svergun, Jill Trewhella
ACTA CRYSTALLOGRAPHICA A-FOUNDATION AND ADVANCES
(2022)
Article
Multidisciplinary Sciences
Ivan Corbeski, Xiaohu Guo, Bruna Eckhardt, Domenico Fasci, Wouter Wiegant, Melissa A. Graewert, Kees Vreeken, Hans Wienk, Dmitri Svergun, Albert J. R. Heck, Haico van Attikum, Rolf Boelens, Titia K. Sixma, Francesca Mattiroli, Hugo van Ingen
Summary: Nucleosome assembly requires specific histone chaperones, but this study found that the acidic domain of DNA repair factor APLF can directly assemble the histone octamer and deposit it on DNA to form nucleosomes, which may be a mechanism for histone chaperone function at sites where chromatin is temporarily disrupted.
Article
Biochemistry & Molecular Biology
Maxime Killer, Giada Finocchio, Haydyn D. T. Mertens, Dmitri I. Svergun, Els Pardon, Jan Steyaert, Christian Loew
Summary: Proton-coupled Oligopeptide Transporters (POTs) mediate the uptake of short di- and tripeptides. This study determined the structure of DtpC and provided insights into its ligand specificity using cryogenic electron microscopy (cryo-EM). The research highlights the value of nanobodies for structure determination of low molecular weight integral membrane proteins.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Stefan R. Marsden, Hein J. Wijma, Michael K. F. Mohr, Ines Justo, Peter-Leon Hagedoorn, Jesper Laustsen, Cy M. Jeffries, Dmitri Svergun, Luuk Mestrom, Duncan G. G. McMillan, Isabel Bento, Ulf Hanefeld
Summary: This study reveals a novel mechanism of enzyme activity regulation, which involves the dynamic movement of the metal cofactor between two coordination spheres without protein scaffold rearrangements. This type of regulation may be widespread but has been largely overlooked.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biochemistry & Molecular Biology
Tomasz H. Benedyk, Viv Connor, Eve R. Caroe, Maria Shamin, Dmitri I. Svergun, Janet E. Deane, Cy M. Jeffries, Colin M. Crump, Stephen C. Graham
Summary: Herpes simplex virus-1 (HSV-1) alters cellular membrane lipid composition during infection. This study demonstrates that a virus-encoded protein, pUL21, promotes the conversion of ceramide (Cer) to sphingomyelin (SM) by activating CERT. The study also reveals the importance of specific protein-protein interactions in HSV-1 mediated sphingolipid metabolism.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Anna Ostendorp, Steffen Ostendorp, Yuan Zhou, Zoe Chaudron, Lukas Wolffram, Khadija Rombi, Linn von Pein, Sven Falke, Cy M. Jeffries, Dmitri I. Svergun, Christian Betzel, Richard J. Morris, Friedrich Kragler, Julia Kehr
Summary: Long-distance RNA transport via the phloem is crucial for communication between different plant tissues. In this study, the phloem-associated RNA chaperone-like (PARCL) protein was characterized and its role in RNA binding and condensate formation was investigated. The results suggest that the function and structure of PARCL can be regulated by modifications.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Iain M. Hay, Maria Shamin, Eve R. Caroe, Ahmed S. A. Mohanned, Dmitri I. Svergun, Cy M. Jeffries, Stephen C. Graham, Hayley J. Sharpe, Janet E. Deane
Summary: Type IIB receptor protein tyrosine phosphatases mediate cell adhesion and signaling through their extracellular and cytoplasmic domains, respectively. The crystal structure of PTPRK has revealed an intermembrane adhesion mode consistent with other family members. Comparison with PTPRM structure suggests that conformational differences between the domains may contribute to homophilic specificity. Analysis of the full-length PTPRM and PTPRK proteins using small-angle X-ray scattering reveals rigid extended conformations and one residue difference at the interaction interface that affects dimer formation.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Chemistry, Physical
Goksin Liu, Erhan Ekmen, Farzaneh Jalalypour, Haydyn D. T. Mertens, Cy M. Jeffries, Dmitri Svergun, Ali Rana Atilgan, Canan Atilgan, Zehra Sayers
Summary: This study combines molecular dynamics (MD) simulations with small angle x-ray scattering (SAXS) measurements to investigate the range of conformations and populations of a pH/ionic strength (IS) sensitive protein. The protein studied is the periplasmic ferric binding protein A (FbpA) involved in iron capture from higher organisms by bacteria. The study reveals the detectable changes in conformational distribution of FbpA under different conditions, but detection of conformational changes due to point mutation D52A and changes in ionic strength has been challenging.
JOURNAL OF CHEMICAL PHYSICS
(2023)
Article
Biochemistry & Molecular Biology
Gabriela Guedez, Gabriele Loers, Cy M. Jeffries, Sandra Kozak, Rob Meijers, Dmitri I. Svergun, Melitta Schachner, Christian Loew
Summary: The cell adhesion molecule L1 plays crucial roles in neural development, regeneration, synaptic plasticity, and tumor cell migration. L1 is a member of the immunoglobulin superfamily and consists of Ig-like domains and fibronectin type III homologous repeats. The second Ig-like domain is involved in cell binding, and the fibronectin type III homologous repeats contribute to signal transduction.
Article
Biochemical Research Methods
Masakazu Fukuda, Melissa A. Graewert, Cy M. Jeffries, Dmitri I. Svergun, Tadao Yamazaki, Akiko Koga, Yuji Yamanaka
Summary: This study investigates the acidic variants of therapeutic monoclonal antibodies (mAbs) using a refolding approach. The results showed that these acidic variants are conformational variants with minor and localized conformational changes.
ANALYTICAL BIOCHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Stefano Da Vela, Giovanni Saudino, Francesca Lucarelli, Lucia Banci, Dmitri I. Svergun, Simone Ciofi-Baffoni
Summary: In humans, the biosynthesis and trafficking of mitochondrial [4Fe-4S]2+ clusters is a highly coordinated process that requires a complex protein machinery. Two [2Fe-2S]2+ clusters are converted into a [4Fe-4S]2+ cluster on an ISCA1-ISCA2 complex. NFU1 is the accessory protein that first receives the [4Fe-4S]2+ cluster from the ISCA1-ISCA2 complex.
JOURNAL OF MOLECULAR BIOLOGY
(2023)