Review
Biochemistry & Molecular Biology
Owen Michael Morris, James Hilary Torpey, Rivka Leah Isaacson
Summary: This review evaluates the anatomy of intrinsically disordered proteins (IDPs) and how their intrinsic properties allow for diversity and different modes of interaction. It also provides a detailed overview of the types of disordered domains and the kinetic and thermodynamic principles governing their formation, with reference to a recent example.
Article
Multidisciplinary Sciences
Thinh D. N. Luong, Suhani Nagpal, Mourad Sadqi, Victor Munoz
Summary: This article introduces a method called "Molecular LEGO" that allows for the dissection of conformational landscapes of unbound intrinsically disordered proteins (IDPs) and provides insights into the functional mechanisms of these proteins. The method was applied to the protein NCBD and revealed specific energetic biases and conformational rheostatic behavior in NCBD's folding landscape, which are likely crucial for its function as a transcriptional coactivator.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
San Hadzi, Jurij Lah
Summary: Intrinsically disordered proteins (IDPs) are common in eukaryotic proteomes and can acquire defined conformations upon binding globular targets. The folding penalty of IDPs in alpha-helical binding motifs has been estimated to be around +2.0 kcal/mol, with a range of 0.7 to 3.5 kcal/mol. Pre-folding and target-bound IDP dynamics reduce the folding cost by approximately half. Understanding the role of folding penalty in IDP-target interactions and estimating this quantity can aid in the design of inhibitors for IDP-target interactions.
Article
Chemistry, Multidisciplinary
Anirban Das, Anju Yadav, Mona Gupta, R. Purushotham, Vishram L. Terse, Vicky Vishvakarma, Sameer Singh, Tathagata Nandi, Arkadeep Banerjee, Kalyaneswar Mandal, Shachi Gosavi, Ranabir Das, Sri Rama Koti Ainavarapu, Sudipta Maiti
Summary: By constructing a xenonucleus based on specific design principles, the refolding speed of ubiquitin protein can be increased. This method provides a new approach for constructing specific folding catalysts for proteins with well-defined folding nuclei.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Physical
Xiaochen Cui, Hao Liu, Ashfaq Ur Rehman, Hai-Feng Chen
Summary: The study suggests that the environment-specific precise force field ESFF1 is more suitable for handling intrinsically disordered proteins (IDPs) than the traditional force field ff14SB, showing a greater diversity in conformation sampling. For folded proteins, both force fields have comparable performances.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2021)
Article
Multidisciplinary Sciences
Zhixin Lei, Haowei Meng, Lulu Liu, Huanan Zhao, Xichen Rao, Yongchang Yan, Hao Wu, Min Liu, Aibin He, Chengqi Yi
Summary: The study reveals that the mitochondrial base editor induces extensive off-target editing in the nuclear genome, highlighting the need to thoroughly define and evaluate the off-target effects of base-editing tools.
Article
Oncology
Junge Deng, Jialiang Zhang, Ying Ye, Kaijing Liu, Lingxing Zeng, Jingyi Huang, Ling Pan, Mei Li, Ruihong Bai, Lisha Zhuang, Xudong Huang, Guandi Wu, Lusheng Wei, Yanfen Zheng, Jiachun Su, Shaoping Zhang, Rufu Chen, Dongxin Lin, Jian Zheng
Summary: This study reveals how aberrant m(6)A modification of the WTAPP1 pseudogene results in increased translation of its protein-coding counterpart to promote Wnt signaling, which contributes to pancreatic cancer progression.
Review
Chemistry, Multidisciplinary
Stefano Gianni, Maria Ines Freiberger, Per Jemth, Diego U. Ferreiro, Peter G. Wolynes, Monika Fuxreiter
Summary: Proteins and their complexes can be described as ensembles that populate an energy landscape, where the diversity arises from the conflicts between interactions shaping the energy landscape. Within this framework, alternative sets of suboptimal contacts can encode specificity without achieving a single structural optimum. The interplay between frustration and fuzziness offers insights into the structural and dynamical continuum of protein assemblies.
ACCOUNTS OF CHEMICAL RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Emily P. P. Bentley, Daniel Scholl, Peter E. E. Wright, Ashok A. A. Deniz
Summary: This study used single-molecule Forster resonance energy transfer (smFRET) to investigate the folding states and DNA binding process of CREB protein. The study found that the basic region and leucine zipper of CREB protein fold differently in response to different binding partners, and that CREB can undergo folding upon binding to nonspecific DNA. Additionally, the study revealed the evidence of long-range interdomain interactions in full-length CREB protein that modulate DNA binding.
Review
Biochemistry & Molecular Biology
Sushmita Basu, Daisuke Kihara, Lukasz Kurgan
Summary: One important characteristic of intrinsically disordered regions (IDRs) is their ability to interact with various molecules. In recent years, the prediction of binding IDRs in protein sequences has become more significant. These prediction tools utilize various predictive architectures, including scoring functions, regular expressions, traditional and deep machine learning, and meta-models. Efforts are currently focused on developing deep neural network-based architectures and expanding the coverage to include RNA, DNA, and lipid-binding IDRs.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2023)
Article
Biochemistry & Molecular Biology
Martin Pacesa, Chun-Han Lin, Antoine Clery, Aakash Saha, Pablo R. Arantes, Katja Bargsten, Matthew J. Irby, Frederic H. -T. Allain, Giulia Palermo, Peter Cameron, Paul D. Donohoue, Martin Jinek
Summary: The crystallographic structures of Cas9 bound to off-target substrates reveal that noncanonical base-pairing interactions within the guide:off-target heteroduplex enable off-target binding. Single-nucleotide deletions in off-target substrates are accommodated by base skipping or multiple noncanonical base pairs. PAM-distal mismatches result in duplex unpairing and induce a conformational change in the Cas9 REC lobe. These insights contribute to the improved rational design of guide RNAs and off-target prediction algorithms.
Article
Chemistry, Physical
Wenning Wang
Summary: Recent progress in atomic MD simulation studies of intrinsically disordered proteins (IDPs) includes the development of force fields and sampling methods, as well as applications in IDP-involved protein-protein interactions. Large-scale simulations and advanced sampling techniques allow for a more accurate estimation of the thermodynamics and kinetics of IDP-mediated protein interactions. The holistic landscape of the binding process of IDPs is emerging through these simulations.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2021)
Article
Biochemistry & Molecular Biology
Sushmita Basu, Tamas Hegedus, Lukasz Kurgan
Summary: In this study, we propose an accurate sequence-based predictor for membrane-binding MoRFs and demonstrate its effectiveness. The tool will contribute to future studies on the abundance, cellular functions, and roles of MemMoRFs in pathological phenomena.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Review
Cell Biology
Andras Zeke, Eva Schad, Tamas Horvath, Rawan Abukhairan, Beata Szabo, Agnes Tantos
Summary: This article summarizes the current state of structural knowledge on the RNA binding modes of disordered protein regions and proposes a classification system based on their sequential and structural properties. Through detailed structural analysis of complexes containing disordered protein regions binding to RNA, two major binding modes representing different recognition strategies and functions were identified. Comparisons with DNA binding disordered proteins revealed key differences and similar binding strategies, suggesting a wider substrate acceptance by these proteins.
WILEY INTERDISCIPLINARY REVIEWS-RNA
(2022)
Article
Chemistry, Physical
Bin Wen, Weiwei Zhang, Yangyang Zhang, Hai Lei, Yi Cao, Wenfei Li, Wei Wang
Summary: This study reveals the molecular mechanism by which disordered proteins achieve high binding cooperativity through a self-effected allostery mechanism. By utilizing one part of the disordered protein as an effector, it triggers conformational coupling and enhances the binding of the remaining part of the same protein, leading to high cooperativity in molecular displacement events.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2022)
Article
Biochemical Research Methods
Anwoy Kumar Mohanty, Dana Vuzman, Laurent Francioli, Christopher Cassa, Agnes Toth-Petroczy, Shamil Sunyaev
Article
Biochemical Research Methods
Thomas A. Hopf, Anna G. Green, Benjamin Schubert, Sophia Mersmann, Charlotta P. I. Schaerfe, John B. Ingraham, Agnes Toth-Petroczy, Kelly Brock, Adam J. Riesselman, Perry Palmedo, Chan Kang, Robert Sheridan, Eli J. Draizen, Christian Dallago, Chris Sander, Debora S. Marks
Article
Biochemistry & Molecular Biology
Csaba Magyar, Aniko Mentes, Erzsebet Ficho, Miklos Cserzo, Istvan Simon
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2018)
Article
Multidisciplinary Sciences
Maria Luisa Romero Romero, Fan Yang, Yu-Ru Lin, Agnes Toth-Petroczy, Igor N. Berezovsky, Alexander Goncearenco, Wen Yang, Alon Wellner, Fanindra Kumar-Deshmukh, Michal Sharon, David Baker, Gabriele Varani, Dan S. Tawfik
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2018)
Article
Biochemistry & Molecular Biology
Balint Meszaros, Laszlo Dobson, Erzsebet Ficho, Gabor E. Tusnady, Zsuzsanna Dosztanyi, Istvan Simon
JOURNAL OF MOLECULAR BIOLOGY
(2019)
Article
Biochemistry & Molecular Biology
Aniko Mentes, Csaba Magyar, Erzsebet Ficho, Istvan Simon
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2019)
Article
Biochemistry & Molecular Biology
Balint Meszaros, Laszlo Dobson, Erzsebet Ficho, Istvan Simon
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2019)
Editorial Material
Biochemistry & Molecular Biology
Istvan Simon
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2020)
Article
Gastroenterology & Hepatology
Jodie Ouahed, Judith R. Kelsen, Waldo A. Spessott, Kameron Kooshesh, Maria L. Sanmillan, Noor Dawany, Kathleen E. Sullivan, Kathryn E. Hamilton, Voytek Slowik, Sergey Nejentsev, Joao Farela Neves, Helena Flores, Wendy K. Chung, Ashley Wilson, Kwame Anyane-Yeboa, Karen Wou, Preti Jain, Michael Field, Sophia Tollefson, Maiah H. Dent, Dalin Li, Takeo Naito, Dermot P. B. McGovern, Andrew C. Kwong, Faith Taliaferro, Jose Ordovas-Montanes, Bruce H. Horwitz, Daniel Kotlarz, Christoph Klein, Jonathan Evans, Jill Dorsey, Neil Warner, Abdul Elkadri, Aleixo M. Muise, Jeffrey Goldsmith, Benjamin Thompson, Karin R. Engelhardt, Andrew J. Cant, Sophie Hambleton, Andrew Barclay, Agnes Toth-Petroczy, Dana Vuzman, Nikkola Carmichael, Corneliu Bodea, Christopher A. Cassa, Marcella Devoto, Richard L. Maas, Edward M. Behrens, Claudio G. Giraudo, Scott B. Snapper
Summary: This study identified damaging variants in the STXBP3 gene in ten patients from five families with a unique clinical presentation of early onset IBD, bilateral sensorineural hearing loss, and recurrent infections. These mutations interfere with intracellular vesicular trafficking, leading to reduced STXBP3 protein expression and defects in cell polarity. Overall, this study highlights the critical role of STXBP3 in VEOIBD, sensorineural hearing loss, and immune dysregulation.
JOURNAL OF CROHNS & COLITIS
(2021)
Article
Biochemistry & Molecular Biology
Csaba Magyar, Aniko Mentes, Miklos Cserzo, Istvan Simon
Summary: Mutual Synergetic Folding (MSF) proteins are a newly discovered class of proteins that exhibit a unique structural organization with both ordered and disordered characteristics. Solvent accessibility, especially of peptide bonds, plays a crucial role in this phenomenon. The local and non-local effects on shielding by amino acid residues during oligomerization steps differ between MSF and globular homodimeric proteins, leading to distinctive structural features.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Editorial Material
Biochemistry & Molecular Biology
Istvan Simon, Csaba Magyar
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Maria Luisa Romero Romero, Cedric Landerer, Jonas Poehls, Agnes Toth-Petroczy
Summary: Errors in DNA replication lead to genetic mutations, while errors in transcription and translation result in phenotypic mutations. Phenotypic mutations occur more frequently but are less understood. The diversity generated by phenotypic mutations can facilitate adaptive evolution and are sometimes involved in regulating protein expression and function. Understanding the protein heterogeneity and phenotypic diversity caused by phenotypic mutations is important for understanding protein evolution and its implications on human health.
Article
Biochemistry & Molecular Biology
Csaba Magyar, Balint Zoltan Nemeth, Miklos Cserzo, Istvan Simon
Summary: Mutual synergistic folding (MSF) proteins are a subclass of disordered proteins that are disordered in their monomeric forms but become ordered in their oligomeric forms. Experimental methods can be used to identify them following their unfolding, which occurs in a single-step cooperative process without stable monomeric intermediates. This study presents a simple protocol using molecular dynamics simulations to indicate whether a protein structure belongs to the MSF subclass.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Genetics & Heredity
Jose Velilla, Michael Mario Marchetti, Agnes Toth-Petroczy, Claire Grosgogeat, Alexis H. Bennett, Nikkola Carmichael, Elicia Estrella, Basil T. Darras, Natasha Y. Frank, Joel Krier, Rachelle Gaudet, Vandana A. Gupta, Richard L. Maas, Shamil Sunyaev, Christopher Cassa, Robert Green, Wolfram Goessling, Alireza Haghighi, Elizabeth Fieg, Calum MacRae, Soumya Raychaudhuri, Christine Seidman, Nikolaos Patsopolous, Onuralp Soylemez
NEUROLOGY-GENETICS
(2019)
Article
Biochemical Research Methods
Eva Schad, Erzsebet Ficho, Rita Pancsa, Istvan Simon, Zsuzsanna Dosztanyi, Balint Meszaros