Review
Biochemistry & Molecular Biology
Ranran Chen, Xinlu Li, Yaqing Yang, Xixi Song, Cheng Wang, Dongdong Qiao
Summary: This paper presents a comprehensive overview of recently published predictors for intrinsically disordered protein (IDP) binding site prediction. The authors collected 30 representative predictors and summarized their databases, features, and algorithms. The predictors were divided into scoring functions, machine learning-based prediction, and consensus approaches, with detailed descriptions of their algorithms and performances. This study not only provides a full picture of the current status of IDP binding prediction, but also serves as a guide for selecting different methods and inspires future development trends and principles.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Norman E. Davey, Leandro Simonetti, Ylva Ivarsson
Summary: Short linear motifs (SLiMs) are unique and ubiquitous protein interaction modules that play important regulatory roles and drive dynamic complex formation. Recent methodological advances have enabled high-throughput discovery of SLiM-mediated interactome in the human cell, filling a significant blind spot in current interactomics data. This article discusses the key methods used to explore the elusive SLiM-mediated interactome and its implications for the field.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Salome Araujo-Abad, Jose L. Neira, Bruno Rizzuti, Pilar Garcia-Morales, Camino de Juan Romero, Patricia Santofimia-Castano, Juan Iovanna
Summary: The nuclear protein 1 (NUPR1) and its paralogue nuclear protein 1-like (NUPR1L) are intrinsically disordered proteins involved in stress-mediated cellular conditions. They interact with peptidyl-arginine deiminase 4 (PADI4) in vitro and in cellulo, and the binding regions have been identified. The NUPR1/PADI4 complex may play important roles in DNA repair, metastasis, and protein citrullination.
JOURNAL OF MOLECULAR BIOLOGY
(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
Chemistry, Multidisciplinary
Li Wan, Yingying Zhu, Wenli Zhang, Wanmeng Mu
Summary: The engineering of a synthetic membraneless organelle platform allows for compartmentalization and spatial organization of pathway enzymes, resulting in increased product titer and yield compared to strains with free-floating enzymes. This platform is achieved by expressing intrinsically disordered proteins in host strains to form artificial membraneless organelles. Different clients can be recruited to these compartments through fusion or interaction with specific protein domains. It provides a promising approach for the development of microbial cell factories and metabolic flux optimization.
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
H. Jane Dyson
Summary: Viruses infect all kingdoms of life and employ disordered proteins to accomplish various functions. Disordered proteins have been discovered in almost all viruses studied, regardless of the viral genome composition or the viral capsid configuration. This review presents a collection of stories illustrating the diverse functions of disordered proteins in viruses, providing a survey of the field's expansion.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Review
Chemistry, Multidisciplinary
Matti Mar, Kateryna Nitsenko, Petur O. Heidarsson
Summary: Eukaryotic transcription factors play a crucial role in integrating molecular feedback and regulating gene expression. They consist of structured DNA-binding domains and long intrinsically disordered regions (IDRs). The dynamic multifunctionality of IDRs is essential for their functions in genome regulation. This review analyzes the chemical features of TF IDRs and their involvement in protein interactions, DNA binding, chromatin opening, and phase separation. Suggestions are given for future research to integrate experiments and simulations in understanding TF functions.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Multidisciplinary Sciences
Luiza Mamigonian Bessa, Serafima Guseva, Aldo R. Camacho-Zarco, Nicola Salvi, Damien Maurin, Laura Marino Perez, Maiia Botova, Anas Malki, Max Nanao, Malene Ringkjobing Jensen, Rob W. H. Ruigrok, Martin Blackledge
Summary: The genome replication and transcription processes of SARS-CoV-2 are important targets for inhibiting the virus. The interaction between the nucleoprotein (N) and the amino-terminal ubiquitin-like domain of nsp3 (Ubl1), which is a cofactor of the replication-transcription complex, has been described at the atomic level. This interaction involves two linear motifs in the linker domain of N, which fold N around Ubl1 to regulate binding to RNA. The identification of these motifs provides future targets for developing innovative strategies against COVID-19.
Article
Biochemistry & Molecular Biology
Patricia Santofimia-Castano, Bruno Rizzuti, Angel L. Pey, Maria Esther Farez-Vidal, Juan L. Iovanna, Jose L. Neira
Summary: Plakophilin 1 (PKP1) and NUPR1 were found to interact in the nucleus of cells, potentially playing a role in carcinogenesis through modulation of PKP1 function. The binding affinity between PKP1 and NUPR1 was determined to be in the low micromolar range, involving specific typtophan residues of PKP1.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Article
Biochemistry & Molecular Biology
Gozde Kibar, Martin Vingron
Summary: Protein-protein interactions (PPIs) are crucial for molecular processes, but the mechanisms of molecular recognition between interacting proteins are poorly understood, making it challenging to predict interactions from sequence. This study proposes a new method using intrinsically disordered regions (IDRs) to tackle this challenge. Using IDR sequences, the researchers predicted PPIs in candidate proteins and divided the prediction problem into subproblems, adapting appropriate strategies. The findings highlight the importance of defining problem type and suggest that accounting for IDRs can aid in predicting features of the intrinsically disordered protein interaction network, accelerating efforts to understand the eukaryotic PPI network.
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
(2023)
Review
Biochemistry & Molecular Biology
Juliana Glavina, Nicolas Palopoli, Lucia Beatriz Chemes
Summary: This article investigates the "arms race" and evolutionary mechanisms between viruses and hosts, focusing on the role of short linear motifs (SLiMs) in viral hijack functions and viral adaptive evolution.
ESSAYS IN BIOCHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Vladimir D. Manyilov, Nikolay S. Ilyinsky, Semen V. Nesterov, Baraa M. G. A. Saqr, Guy W. Dayhoff, Egor V. Zinovev, Simon S. Matrenok, Alexander V. Fonin, Irina M. Kuznetsova, Konstantin K. Turoverov, Valentin Ivanovich, Vladimir N. Uversky
Summary: This article examines the impact of intrinsically disordered proteins and regions on aging-related processes. The findings indicate that these disordered components play significant roles in aging, particularly in genome regulation.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Biochemical Research Methods
Fuhao Zhang, Bi Zhao, Wenbo Shi, Min Li, Lukasz Kurgan
Summary: This study presents the development of an innovative deep multi-task architecture, DeepDISOBind, which accurately predicts intrinsically disordered regions (IDRs) that interact with nucleic acids and proteins in protein sequences. The results show significant improvements in predictive accuracy compared to single-task designs and existing methods. Analysis of human proteome data demonstrates the ability of DeepDISOBind to accurately predict DNA- and RNA-binding proteins and protein hubs.
BRIEFINGS IN BIOINFORMATICS
(2022)
Article
Biochemistry & Molecular Biology
Prakash Kulkarni, Amita Behal, Atish Mohanty, Ravi Salgia, Aurora M. Nedelcu, Vladimir N. Uversky
Summary: Intrinsically disordered proteins (IDPs) play crucial roles in the early evolution of complex multicellularity by rewiring cellular protein interaction networks and facilitating the co-option of ancestral pathways for specialized multicellular functions.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Biophysics
Francesco Pesce, Estella A. Newcombe, Pernille Seiffert, Emil E. Tranchant, Johan G. Olsen, Christy R. Grace, Birthe B. Kragelund, Kresten Lindorff-Larsen
Summary: Diffusion measurements by pulsed-field gradient NMR and fluorescence correlation spectroscopy can be used to probe the hydrodynamic radius of proteins. To tackle the accuracy uncertainty issue in computing the hydrodynamic radius from atomic coordinates, conformational ensembles of intrinsically disordered proteins were built and compared with measurements of compaction. The Kirkwood-Riseman equation was found to provide the best description of the hydrodynamic radius probed by pulsed-field gradient NMR ex-periments.
BIOPHYSICAL JOURNAL
(2023)
Review
Oncology
Amanda B. Abildgaard, Sofie Nielsen, Inge Bernstein, Amelie Stein, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen
Summary: Accurate diagnosis and clinical interpretation of individual variants are crucial for the treatment of Lynch syndrome, a heritable cancer disease. Traditional protein variant classification methods are complex, but recent developments in high-throughput technologies and computational prediction tools offer new possibilities for assessing variants of unknown significance and gaining mechanistic insights into the disease.
BRITISH JOURNAL OF CANCER
(2023)
Article
Biochemistry & Molecular Biology
Amanda B. Abildgaard, Vasileios Voutsinos, Soren D. Petersen, Fia B. Larsen, Caroline Kampmeyer, Kristoffer E. Johansson, Amelie Stein, Tommer Ravid, Claes Andreasson, Michael K. Jensen, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen
Summary: Protein quality control (PQC) degrons are short protein segments that target misfolded proteins for proteasomal degradation, and chaperone-binding regions may function as PQC degrons. A canonical Hsp70-binding motif, the APPY peptide, functions as a dose-dependent PQC degron in yeast and human cells. The number of exposed Hsp70-binding sites in the yeast proteome correlates with reduced protein abundance and half-life.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Kristoffer E. Johansson, Bayan Mashahreh, Rasmus Hartmann-Petersen, Tommer Ravid, Kresten Lindorff-Larsen
Summary: Effective proteome homeostasis is crucial for cell and organism survival. Cells have efficient quality control systems to monitor and remove misfolded proteins. The nature and sequence properties of quality-control degrons are still unknown.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Article
Biology
Steffie Elkjaer, Amanda D. D. Due, Lise F. F. Christensen, Frederik F. Theisen, Lasse Staby, Birthe B. B. Kragelund, Karen Skriver
Summary: Evolution-guided mutagenesis and biophysical analysis reveal that residual helical structure in the binding region of an intrinsically disordered protein regulates the lifetime of its complex by affecting its dissociation.
COMMUNICATIONS BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Fia B. Larsen, Matteo Cagiada, Jonas Dideriksen, Amelie Stein, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen
Summary: Catechol-O-methyltransferase (COMT) is an important enzyme involved in the metabolism of neurotransmitters and catecholamine drugs, and its variation can affect pharmacokinetics and drug availability.
Review
Biotechnology & Applied Microbiology
Yixin Rong, Sheila Ingemann Jensen, Kresten Lindorff-Larsen, Alex Toftgaard Nielsen
Summary: The expression of correctly folded and functional heterologous proteins is crucial in biotechnological production processes. Bacterial platform organisms like E. coli are commonly used due to their proven suitability at an industrial scale, but can suffer from protein aggregation and low functional protein levels. This review explores cellular mechanisms influencing protein folding and expression across different organisms, and discusses experimental methods to improve protein folding, such as codon optimization and chaperone co-production.
BIOTECHNOLOGY ADVANCES
(2023)
Article
Biochemistry & Molecular Biology
Caroline Kampmeyer, Martin Gronbaek-Thygesen, Nicole Oelerich, Michael H. Tatham, Matteo Cagiada, Kresten Lindorff-Larsen, Wouter Boomsma, Kay Hofmann, Rasmus Hartmann-Petersen
Summary: Lysine is a common amino acid in the human proteome, but there are proteins that lack lysine residues. These lysine deserts are common in intrinsically disordered proteins involved in the ubiquitin-proteasome system. Introducing lysine residues can increase ubiquitylation of these proteins, and their stability and function may be affected. This avoidance of lysine residues may be an evolutionary mechanism to prevent unnecessary ubiquitylation in proteins closely involved with the ubiquitylation machinery.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Kristoffer E. Johansson, Kresten Lindorff-Larsen, Jakob R. Winther
Summary: Identifying amino acid substitutions that improve both stability and function of a protein is a challenge in protein engineering. The Global Multi-Mutant Analysis (GMMA) method is used to identify beneficial substitutions across a large library of protein variants by analyzing multiply-substituted variants. Experimental results showed that the top-ranking substitutions progressively enhanced the function of GFP. Large libraries of multiply-substituted variants could provide valuable information for protein engineering.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Letter
Biochemistry & Molecular Biology
Kaare Teilum, Johan G. Olsen, Birthe B. Kragelund
Article
Biochemistry & Molecular Biology
Yulian Gavrilov, Andreas Prestel, Kresten Lindorff-Larsen, Kaare Teilum
Summary: Slow conformational changes are important for protein function, but their impact on the overall folding stability is not well understood. This study investigates the effects of L49I and I57V substitutions on the slow conformational dynamics of CI2. The results show that these substitutions have minimal impact on the structure of the excited state, but the stability of the excited state is influenced by the stability of the main state. The interactions between substituted residues and water molecules play a role in linking subtle structural changes to slow conformational changes in the protein.
Article
Biology
Raul Araya-Secchi, Katrine Bugge, Pernille Seiffert, Amalie Petry, Gitte W. Haxholm, Kresten Lindorff-Larsen, Stine Falsig Pedersen, Lise Arleth, Birthe B. Kragelund
Summary: This study investigates the role of lipids in PRLR signaling and finds that co-structure formation locks the disordered domain of PRLR in an extended structure, enabling signal relay.
Article
Biochemistry & Molecular Biology
Nina L. Jacobsen, Magnus Bloch, Peter S. Millard, Sarah F. Ruidiaz, Jonas D. Elsborg, Wouter Boomsma, Ruth Hendus-Altenburger, Rasmus Hartmann-Petersen, Birthe B. Kragelund
Summary: This study found that Schizosaccharomyces pombe Dss1 is phosphorylated by casein kinase 2 at three threonine sites in its linker region. The phosphorylation does not affect its ubiquitin binding ability, but slightly destabilizes the C-terminal alpha-helix and directly interacts with the forkhead-associated domain of the RING-FHA E3-ubiquitin ligase defective in mitosis 1 (Dma1). These phosphorylation sites are absent in human Dss1.
Correction
Multidisciplinary Sciences
Andrea Sottini, Alessandro Borgia, Madeleine B. Borgia, Katrine Bugge, Daniel Nettels, Aritra Chowdhury, Petur O. Heidarsson, Franziska Zosel, Robert B. Best, Birthe B. Kragelund, Benjamin Schuler
NATURE COMMUNICATIONS
(2023)
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
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)