Article
Biochemistry & Molecular Biology
Alexandra D. Brown, Connor Cranstone, Denis J. Dupre, David N. Langelaan
Summary: The study investigates the interaction between β-catenin and CBP/p300, and determines that the C-terminal region of β-catenin binds to the TAZ1 and TAZ2 domains of CBP/p300. The results provide insights into the gene regulation mechanism of β-catenin and offer a framework for developing methods to block β-catenin dependent signaling.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Biochemical Research Methods
Lei Yu, Rafael Bruschweiler
Summary: The article investigates the molecular simulation of two intrinsically disordered proteins (IDPs) and validates them with experimental data. The results show that the new molecular dynamics simulation method can generate highly realistic protein conformational ensembles, which are of great significance for understanding the biological function of IDPs.
PLOS COMPUTATIONAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Michael W. Risor, Ariane L. Jansma, Natasha Medici, Brittany Thomas, H. Jane Dyson, Peter E. Wright
Summary: The N-terminal region of the HPV16 E7 protein interacts with cellular factors and causes oncogenic transformation of host cells; despite high nanomolar affinity with TAZ2, the complex is disordered and highly dynamic; the fuzzy nature of the complex reflects the promiscuous binding repertoire of viral proteins.
Article
Biochemistry & Molecular Biology
Jing Zhao, Xinyue Liu, Alan Blayney, Yumeng Zhang, Lauren Gandy, Paige Olivia Mirsky, Nathan Smith, Fuming Zhang, Robert J. Linhardt, Jianhan Chen, Christopher Baines, Stewart N. Loh, Chunyu Wang
Summary: The mitochondrial permeability transition pore (mPTP) plays crucial roles in various diseases. Cyclophilin D is confirmed as the only component of mPTP. Previous studies have reported that p53 interacts with CypD through its DNA-binding domain (DBD). However, this study found that the N-terminal domain (NTD) of p53 is the major binding site for CypD. The study provides insights into the dynamic interface between NTD and CypD.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Biochemical Research Methods
Fan Jin, Frauke Grater
Summary: The study found that multi-site phosphorylation causes V-shaped changes in collapse propensity of all proteins based on their initial net charge, expanding neutral or overall negatively charged IDPs and shrinking positively charged IDPs. In two of the IDPs, only two biologically relevant phosphorylation sites are enough to significantly expose the adjacent negatively charged active site, increasing the likelihood of interaction with other binding partners.
PLOS COMPUTATIONAL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Jing Zhao, Alan Blayney, Xiaorong Liu, Lauren Gandy, Weihua Jin, Lufeng Yan, Jeung-Hoi Ha, Ashley J. Canning, Michael Connelly, Chao Yang, Xinyue Liu, Yuanyuan Xiao, Michael S. Cosgrove, Sozanne R. Solmaz, Yingkai Zhang, David Ban, Jianhan Chen, Stewart N. Loh, Chunyu Wang
Summary: Epigallocatechin gallate (EGCG) in green tea induces apoptosis in cancerous cells through a direct interaction with the tumor suppressor p53, inhibiting p53 ubiquitination by its regulatory E3 ligase MDM2 and stabilizing p53 for anti-tumor activity.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Multidisciplinary
Hao Ruan, Chen Yu, Xiaogang Niu, Weilin Zhang, Hanzhong Liu, Limin Chen, Ruoyao Xiong, Qi Sun, Changwen Jin, Ying Liu, Luhua Lai
Summary: In this study, a hierarchical computational strategy for IDP drug discovery was proposed and successfully applied to identify two compounds that bind p53 TAD1 and restore wild-type p53 function. The study demonstrates the efficiency of IDPDVS in IDP drug discovery and the potential for direct targeting of p53 TAD1 by small molecules.
Review
Chemistry, Multidisciplinary
Hanping Wang, Ruoyao Xiong, Luhua Lai
Summary: Intrinsically disordered proteins (IDPs) are proteins without well-defined structures under physiological conditions, but they play important biological functions. They can form fuzzy complexes, contribute to the formation of membraneless organelles, and serve as hubs in protein-protein interaction networks. Targeting IDPs for drug design is challenging due to their highly dynamic structures and fuzzy interactions. However, turning IDPs into druggable targets opens up opportunities for novel drug discovery. Integrative structural biology approaches have been used to uncover the dynamic structures and interactions of IDPs. Several IDP-targeting drugs have advanced into clinical trials, and new computational methods are being developed for efficient discovery and optimization of specific and potent ligands for IDPs. Understanding the dynamic structures and interactions of IDPs is crucial for drug development.
WILEY INTERDISCIPLINARY REVIEWS-COMPUTATIONAL MOLECULAR SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Ellen Rieloff, Marie Skepo
Summary: Phosphorylation plays a crucial role in regulating the function of intrinsically disordered proteins, with the distribution of phosphorylated and positively charged residues throughout the sequence impacting the formation of salt bridges. Understanding the structural implications of phosphorylation remains a challenge, as factors beyond net charge, such as specific residue interactions, can influence the global dimensions of disordered proteins.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Estella A. Newcombe, Catarina B. Fernandes, Jeppe E. Lundsgaard, Inna Brakti, Kresten Lindorff-Larsen, Annette E. Langkilde, Karen Skriver, Birthe B. Kragelund
Summary: Motifs within proteins help categorize their functions;Intrinsically disordered proteins (IDPs) rich in short linear motifs with various roles;Study found calcium-binding motifs in IDPs may serve various underreported structural and functional roles.
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)
Article
Chemistry, Physical
Pablo Herrera-Nieto, Adria Perez, Gianni De Fabritiis
Summary: Intrinsically disordered proteins participate in biological processes by folding upon binding to other proteins. However, the process of coupled folding and binding is still poorly understood. This study used a new approach to reconstruct the binding and folding process between disordered protein c-Myb and CREB-binding protein. The long-term dynamic process revealed that a short stretch of amino acids on c-Myb forms a folded α-helix during binding, and initial native contacts formed by leucine residues, especially Leu298-Leu302, facilitate the binding and folding of the rest of the peptide.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Physical
Antonio B. Oliveira, Xingcheng Lin, Prakash Kulkarni, Jose N. Onuchic, Susmita Roy, Vitor B. P. Leite
Summary: The newly developed energy landscape visualization method ELViM is applied to explore the frustrated energy landscapes of the intrinsically disordered protein PAGE4. Analysis of atomistic trajectories and energy landscapes using ELViM reveals how phosphorylation affects the conformational diversity and functional mechanisms of different phosphoforms of PAGE4, shedding light on their interactions with proteins such as c-Jun.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2021)
Article
Cell Biology
Morgan A. Gingerich, Xueying Liu, Biaoxin Chai, Gemma L. Pearson, Michael P. Vincent, Tracy Stromer, Jie Zhu, Vaibhav Sidarala, Aaron Renberg, Debashish Sahu, Daniel J. Klionsky, Santiago Schnell, Scott A. Soleimanpour
Summary: CLEC16A regulates mitochondrial health through mitophagy and is associated with over 20 human diseases. This study reveals the importance of a C-terminal intrinsically disordered protein region (IDPR) in CLEC16A for mitochondrial quality control. The stability of CLEC16A is dependent on proline bias within the C-terminal IDPR.
Article
Chemistry, Multidisciplinary
Fanni Sebak, Peter Ecsedi, Wolfgang Bermel, Burkhard Luy, Laszlo Nyitray, Andrea Bodor
Summary: This study introduces two new NMR experiments to identify proline cis/trans isomers in proteins, detecting minor conformers present in 4-15%, and analyzes the impact of CK2 phosphorylation on the cis/trans-proline equilibrium. Statistical analysis indicates that the amino acid type also affects the distribution of cis/trans-proline.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biochemistry & Molecular Biology
Amrinder Singh, Maria A. Martinez-Yamout, Peter E. Wright, H. Jane Dyson
Summary: NF-kappa B is a central mediator in cellular signaling pathways, which remains sequestered in the cytoplasm in complex with I kappa B alpha under resting conditions. Activation of NF-kappa B involves phosphorylation, ubiquitination, and degradation of I kappa B alpha, leading to its translocation to the nucleus. A long noncoding RNA, NKILA, was found to modulate the NF-kappa B signaling circuit by interacting with the NF kappa B-I kappa B alpha complex in the cytoplasm.
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
Shunji Suetaka, Yoshiki Oka, Tomoko Kunihara, Yuuki Hayashi, Munehito Arai
Summary: The researchers have developed an inhibitor to disrupt the interaction between c-Myb and KIX by stabilizing the helical structure of c-Myb using theoretical predictions and mutation design. These findings suggest that designing helical peptide inhibitors, particularly through conservative amino acid substitutions, is a simple and effective strategy for developing antitumor drugs.
SCIENTIFIC REPORTS
(2022)
Article
Multidisciplinary Sciences
Yoshiki Oka, Hiroko Yukawa, Hisashi Kudo, Koji Ooka, Manami Wada, Shunji Suetaka, Mari Chang, Hidenobu Kawai, Ryouji Tanaka, Masahiro Ichikawa, Takahisa Suzuki, Yuuki Hayashi, Akihiro Handa, Munehito Arai
Summary: SEC and SEC-SAXS were used to differentiate between unpasteurized and pasteurized frozen whole eggs. The protein structures in pasteurized eggs are sensitive to temperature changes.
SCIENTIFIC REPORTS
(2022)
Article
Biochemistry & Molecular Biology
Daisuke Tashiro, Shunji Suetaka, Nao Sato, Koji Ooka, Tomoko Kunihara, Hisashi Kudo, Junichi Inatomi, Yuuki Hayashi, Munehito Arai
Summary: Human epidermal growth factor receptors (HER/ERBB) play a vital role in cell proliferation and cancer, but overexpression can cause cancer. Herstatin, an alternative splice variant of HER2, has been identified as a tumor suppressor. This study reveals that a specific domain of herstatin, called Int8, is intrinsically disordered but has a residual helical structure. The research also suggests that a mutant form of Int8, R371I, that is defective in binding to HER2, may lead to the loss of its tumor-suppressive activity.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Koji Ooka, Runjing Liu, Munehito Arai
Summary: The WSME model is a promising statistical mechanical model that can calculate the free-energy landscapes of proteins, providing a comprehensive understanding of protein folding mechanisms and structure stability. By predicting protein folding mechanisms and associated conformational changes, this model is expected to be useful in both basic research and applications.
Article
Biochemistry & Molecular Biology
Alexander S. Krois, Sangho Park, Maria A. Martinez-Yamout, H. Jane Dyson, Peter E. Wright
Summary: The structure and interactions of the C-terminal region of p53 protein have been studied. Full-length p53 constructs were generated using trans-intein splicing and isotopically labeled for NMR analysis. This study provides high-resolution insights into the behavior of the C-terminal domains within the full-length protein and the molecular basis of its interactions with DNA.
Article
Chemistry, Physical
Derrick W. Meinhold, Daniel J. Felitsky, H. Jane Dyson, Peter E. Wright
Summary: The early events in protein folding, especially in the unfolded state, are not well understood. The study used NMR experiments to investigate the transient local collapse events in the unfolded-state of apomyoglobin. The findings suggest that there are pH-dependent transient intramolecular contacts occurring at a microsecond to millisecond time scale. The rapid and concomitant chain collapse and secondary structure formation were observed in the early folding intermediates.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Review
Biotechnology & Applied Microbiology
Yuuki Hayashi, Munehito Arai
Summary: The use of biologically produced alkanes as an alternative to petroleum has gained significant attention. The discovery of the alkane synthesis pathway in cyanobacteria and the proteins involved, acyl-(acyl carrier protein [ACP]) reductase (AAR) and aldehyde deformylating oxygenase (ADO), has opened up new possibilities for alkane production through genetic modification. This review summarizes recent findings on the structures and catalytic mechanisms of AAR and ADO, outlines the complex formation and efficient transfer of insoluble aldehydes between AAR and ADO, and describes advancements in protein engineering studies to improve alkane production in genetically engineered microorganisms. The role of alkanes in cyanobacteria and future perspectives for bioalkane production using AAR and ADO are also discussed.
MICROBIAL CELL FACTORIES
(2022)
Review
Chemistry, Multidisciplinary
H. Jane Dyson, Peter E. Wright
Summary: It is difficult to assess the role of individual mentors in the development of important ideas. However, in the case of the realization that proteins can be functional without stable folding, the influence of Richard Lerner and the collaborative work in the 1980s on immunogenic peptides provided a foundation for understanding the nature of polypeptides in water solutions. This led to the formulation and development of the concept of intrinsic disorder in proteins, and the recognition of its functional advantage in cellular processes.
ISRAEL JOURNAL OF CHEMISTRY
(2023)
Article
Microbiology
Daiki Matsuike, Yuhei O. Tahara, Takahiro Nonaka, Heng Ning Wu, Tasuku Hamaguchi, Hisashi Kudo, Yuuki Hayashi, Munehito Arai, Makoto Miyata
Summary: In this study, the function and structure of the surface protein Gli123 in Mycoplasma mobile were investigated. It was found that Gli123 has two distinct globular and rod-like structures, and it plays a crucial role in the assembly of the surface gliding machinery through the evolution of repetitive lipoprotein units.
JOURNAL OF BACTERIOLOGY
(2023)
Article
Multidisciplinary Sciences
Nao Sato, Shunji Suetaka, Yuuki Hayashi, Munehito Arai
Summary: The researchers designed a KIX inhibitor by performing theoretical saturation mutagenesis and found that the T2857W mutant of the MLL TAD peptide had the highest binding affinity for KIX. This peptide also showed a significant inhibitory effect on the KIX-MLL interaction. This approach may be useful for developing helical peptides that can inhibit protein-protein interactions involved in disease progression.
SCIENTIFIC REPORTS
(2023)
Article
Biochemistry & Molecular Biology
Takahisa Suzuki, Masataka Yoshimura, Hiroki Hoshino, Keiji Fushimi, Munehito Arai, Rei Narikawa
Summary: This study identified a unique variant molecule of CBCR GAF domain that showed far-red/blue reversible photoconversion by introducing a second Cys residue near the chromophore. This discovery provides insights into the spectral tuning mechanism of CBCRs and contributes to tool development.
Article
Multidisciplinary Sciences
Koji Ooka, Munehito Arai
Summary: Recent advancements in using deep neural networks for accurate protein structure prediction have made significant progress in solving the structure prediction aspect of the protein folding problem. However, predicting the detailed mechanisms of protein folding into specific native structures remains challenging, especially for multidomain proteins that make up the majority of proteomes. In this study, a simple structure-based statistical mechanical model was developed to incorporate nonlocal interactions that drive the folding of multidomain proteins. The model successfully predicted protein folding processes consistent with experimental results, overcoming limitations in protein size and shape. Additionally, slight modifications allowed for the prediction of disulfide-oxidative and disulfide-intact protein folding, providing insight into folding mechanisms beyond experimental reproduction. Therefore, these physics-based models enable accurate prediction of protein folding mechanisms with low computational complexity and pave the way for solving the folding process aspect of the protein folding problem.
NATURE COMMUNICATIONS
(2023)
Article
Plant Sciences
Takayuki Shimizu, Yuuki Hayashi, Munehito Arai, Shawn E. McGlynn, Tatsuru Masuda, Shinji Masuda
Summary: The study revealed that SqrR can bind heme, reducing its DNA-binding affinity and altering its regulatory activity. Changes in intracellular heme concentration are associated with a significant reduction in SqrR-mediated transcriptional repression.
PLANT AND CELL PHYSIOLOGY
(2021)