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)
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)
Review
Biochemistry & Molecular Biology
Hamza El Hadi, Anne Freund, Steffen Desch, Holger Thiele, Nicolas Majunke
Summary: Cardiomyopathies are a diverse group of heart muscle disorders with potentially fatal consequences such as arrhythmias and heart failure. They are a leading cause of heart transplantation worldwide. Recent advancements in understanding the molecular basis and diagnostic evaluation have paved the way for targeted therapies. However, further research is needed to improve risk assessment and prevention strategies for sudden cardiac death.
Article
Biochemistry & Molecular Biology
Soumyanetra Chandra, Kavyashree Manjunath, Aparna Asok, Raghavan Varadarajan
Summary: Unlike globular proteins, the mutational effects on IDPs' function are not well-studied. By conducting Deep Mutational Scanning on a mutant library of the CcdA IDP displayed on yeast surface, the study sheds light on the sequence-function relationships. The research also reveals that a single ligand concentration can be used to quantitatively estimate the relative binding constants for a large number of protein variants, thanks to IDPs' extended interface.
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)
Review
Medicine, General & Internal
Enrica Chiti, Marco Paolo, Emanuela Turillazzi, Anna Rocchi
Summary: MiRNAs are small non-coding RNAs involved in regulating biochemical pathways in the human body; their levels can be altered due to pathophysiological mechanisms, making them potential biomarkers for cardiac diseases and other pathological conditions. This review summarizes findings of miRNA biomarkers in the three most common structural cardiomyopathies.
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)
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
Aakriti Upadhyay, Chinwe Ekenna
Summary: Understanding the binding behavior and conformational dynamics of intrinsically disordered proteins (IDPs) is crucial. We proposed an algorithm that explores IDP binding behavior with protein complexes by extracting topological and geometric features from the protein surface model. Our method outperformed the compared methods in computation performance and binding affinity in experimental conformations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Carlos Pintado-Grima, Oriol Barcenas, Salvador Ventura
Summary: This study conducted a large-scale in-silico analysis of the effect of solution pH on the solubility and disorder of intrinsically disordered regions (IDRs) involved in liquid-liquid phase separation (LLPS). The results showed that LLPS-DRs have maximum solubility around physiological pH, where LLPS often occurs, and significant differences were found between proteins that can phase-separate by themselves or those that require a partner.
Review
Cardiac & Cardiovascular Systems
Seitaro Nomura, Minoru Ono
Summary: Cardiomyopathy develops through a combination of genetic and environmental factors. Genetic testing can identify causative genes in about half of the cases and predict clinical prognosis. Genome-wide genetic research is crucial for accurate disease risk assessment, as cardiomyopathy is caused by both single rare variants and combinations of multiple common variants. Single-cell analysis research is advancing rapidly, and the combination of genomic analysis and single-cell molecular profiling is expected to contribute to more detailed stratification of cardiomyopathy.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(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
Health Care Sciences & Services
Angelika Weis, Svenja Krueck, Gregor Dombrowsky, Anne Schaenzer, Christian Jux, Anselm Uebing, Inga Voges, Marc-Phillip Hitz, Stefan Rupp
Summary: The study focuses on three families with dilated cardiomyopathy (DCM) and pathogenic variants in the TNNT2 gene. These variants have high penetrance and poor prognosis, with the majority of patients dying or receiving heart transplantation. The age of onset varies from neonatal period to 52 years old. Family screening of patients with DCM improves risk assessment and treatment outcomes.
JOURNAL OF PERSONALIZED MEDICINE
(2023)
Article
Chemistry, Multidisciplinary
Carmen Suay-Corredera, Maria Rosaria Pricolo, Diana Velazquez-Carreras, Divya Pathak, Neha Nandwani, Carolina Pimenta-Lopes, David Sanchez-Ortiz, Inigo Urrutia-Irazabal, Silvia Vilches, Fernando Dominguez, Giulia Frisso, Lorenzo Monserrat, Pablo Garcia-Pavia, David de Sancho, James A. Spudich, Kathleen M. Ruppel, Elias Herrero-Galan, Jorge Alegre-Cebollada
Summary: Hypertrophic cardiomyopathy (HCM) is a disease caused by mutations in sarcomeric proteins, with many mutations not affecting protein structure or stability. Research shows that these mutations may disrupt the nanomechanics of cMyBP-C, affecting its regulatory role in actomyosin filaments.
Article
Biochemistry & Molecular Biology
Andrey K. Tsaturyan, Elena V. Zaklyazminskaya, Margarita E. Polyak, Galina V. Kopylova, Daniil V. Shchepkin, Anastasia M. Kochurova, Anastasiia D. Gonchar, Sergey Y. Kleymenov, Natalia A. Koubasova, Sergey Y. Bershitsky, Alexander M. Matyushenko, Dmitrii I. Levitsky
Summary: The study identified a new variant in the TPM1 gene, which is associated with HCM. The variant increased the thermal stability of the Tpm molecule and its affinity for F-actin was unaffected. However, it increased the Ca2+ sensitivity of filament sliding and impaired its inhibition at low Ca2+ concentration.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Cardiac & Cardiovascular Systems
Steven Marston, Jose Renato Pinto
Summary: In cardiac muscle, the action of adrenaline on beta 1 receptors is essential for enhancing contractility, heart rate, and relaxation through PKA activation. Lusitropy plays a crucial role in shortening the heartbeat during increased heart rate. PKA phosphorylates TnI and PLB, leading to faster relaxation and Ca2+ removal. This review examines the relationship between decreased lusitropy and cardiac dysfunction, discusses the impact of mutations in PLB and thin filament proteins, and evaluates the therapeutic potential of restoring suppressed lusitropy.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2023)
Article
Multidisciplinary Sciences
Maicon Landim-Vieira, Weikang Ma, Taejeong Song, Hosna Rastegarpouyani, Henry Gong, Isabella Leite Coscarella, Sylvia J. P. Bogaards, Stefan P. Conijn, Coen A. C. Ottenheijm, Hyun S. Hwang, Maria Papadaki, Bjorn C. Knollmann, Sakthivel Sadayappan, Thomas C. Irving, Vitold E. Galkin, P. Bryant Chase, Jose Renato Pinto
Summary: Missense variant Ile79Asn in human cardiac troponin T (cTnT-I79N) is associated with hypertrophic cardiomyopathy and sudden cardiac arrest. A recent study showed that cTnT-I79N destabilizes the relaxed state of the cardiac thin filament, resulting in increased myofilament Ca2+ sensitivity and slower crossbridge kinetics. This is likely due to the weakening of the interaction between the TnT1 loop and actin filament.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Li Zhu, Maicon Landim-Vieira, Michelle Rodriguez Garcia, Jose R. Pinto, Joseph M. Chalovich
Summary: The basic C-terminal region of human troponinT (TnT) plays a crucial role in regulating actomyosin ATPase activity in response to calcium levels. Phosphomimetic-like mutants of TnT were generated to identify key basic residues in this region. The S275D and T277D mutants showed the highest level of ATPase activation, while the T284D mutant had the smallest effect. These findings suggest that negative charge placement in the C-terminal region of TnT, particularly near the IT helix and adjacent to basic residues, significantly impacts its regulatory function.
Article
Biochemistry & Molecular Biology
Michelle Rodriguez Garcia, Jeffrey Schmeckpeper, Maicon Landim-Vieira, Isabella Leite Coscarella, Xuan Fang, Weikang Ma, Payton A. Spran, Shengyao Yuan, Lin Qi, Aida Rahimi Kahmini, M. Benjamin Shoemaker, James B. Atkinson, Peter M. Kekenes-Huskey, Thomas C. Irving, Prescott Bryant Chase, Bjoern C. Knollmann, Jose Renato Pinto
Summary: In this study, the effects of an ACTN2 missense variant (p.A868T) on cardiac muscle structure and function were investigated. The results showed small structural changes in cardiomyocytes at the ultrastructural level, as well as increased myofilament Ca-2+ sensitivity and faster rates of tension redevelopment in the ACTN2 A868T variant cardiac tissue. Molecular dynamics simulations suggested that the mutation may alter the conformation associated with titin binding. This study establishes the role of alpha-actinin 2 in modulating cross-bridge kinetics and force development in the human myocardium, and provides insights into its involvement in the development of cardiac disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Meeting Abstract
Biophysics
Cristina M. Risi, Betty Belknap, Howard D. White, J. Renato D. Pinto, Prescott B. Chase, Vitold E. Galkin
BIOPHYSICAL JOURNAL
(2023)
Meeting Abstract
Biophysics
Isabella Leite Coscarella, Prescott B. Chase, Lili Wang, Bjorn C. Knollmann, Jerome Irianto, J. Renato D. Pinto
BIOPHYSICAL JOURNAL
(2023)
Meeting Abstract
Biophysics
Michelle C. Rodriguez Garcia, Jeffrey Schmeckpeper, Maicon Landim-Vieira, Isabella Leite Coscarella, Xuan Fang, Weikang Ma, Aida Rahimi Kahmini, Lili Wang, Moore B. Shoemaker, James B. Atkinson, Peter Kekenes-Huskey, Thomas Irving, Prescott B. Chase, Bjorn C. Knollmann, J. Renato Pinto
BIOPHYSICAL JOURNAL
(2023)
Meeting Abstract
Biophysics
Yun Shi, Sarah A. Kosta, Jose R. Pinto, Vitold E. Galkin, Kenneth S. Campbell, Prescott B. Chase
BIOPHYSICAL JOURNAL
(2023)
Article
Chemistry, Physical
Pablo Dominguez-Garcia, Jose R. Pinto, Ana Akrap, Sylvia Jeney
Summary: We used single-particle optical trapping interferometry to investigate the local fluctuations of filamentous actin (F-actin), especially the skeletal thin filament. The experiments revealed the power-law behaviors of mean square displacement, loss modulus, and velocity autocorrelation function (VAF) of the trapped microprobes in the fluid. We obtained subdiffusive power-law exponents and discussed their deviations in relation to characteristic length scales and properties of the F-actin networks and probes, as well as the different power-law exponents detected in the VAFs. Furthermore, we observed that the thin filament composed of tropomyosin (Tm) and troponin (Tn) coupled to F-actin in the presence of Ca2+ showed less dispersed exponent values, indicating filament stabilization.
Review
Biochemistry & Molecular Biology
Taejeong Song, Maicon Landim-Vieira, Mustafa Ozdemir, Caroline Gott, Onur Kanisicak, Jose Renato Pinto, Sakthivel Sadayappan
Summary: Skeletal muscle, a complex muscle type, is targeted by various diseases, including distal arthrogryposes (DAs), which involve contractures in limb joints. DAs are inherited and caused by mutations in genes encoding sarcomeric proteins, such as myosin heavy chains and myosin binding protein-C (MYBPC). This review focuses on MYBPC paralogs, specifically sMyBP-C and fMyBP-C, and their roles in skeletal muscle function, including contraction regulation and potential future research directions.
EXPERIMENTAL AND MOLECULAR MEDICINE
(2023)
Article
Multidisciplinary Sciences
Cristina M. Risi, Betty Belknap, Howard D. White, Kelly Dryden, Jose R. Pinto, P. Bryant Chase, Vitold E. Galkin
Summary: Cardiac contraction relies on molecular interactions between thin and thick filaments. This study provides a structural description of the cardiac thin filament junction region and offers insights into cardiac diseases.
Article
Multidisciplinary Sciences
Cristina M. Risi, Betty Belknap, Howard D. White, Kelly Dryden, Jose R. Pinto, P. Bryant Chase, Vitold E. Galkin
Summary: Cardiac contraction relies on the interactions among sarcomeric proteins, and the rising and falling levels of intracellular Ca2+. We provide novel insights into the structure of the cardiac thin filament (cTF) junction region, revealing the interactions between adjacent tropomyosin (Tm) molecules and between Tm and actin. Our findings highlight the importance of TnT1 in stabilizing the Tm overlap region and the relaxed state of cTF.
Meeting Abstract
Biophysics
Maicon Landim-Vieira, Weikang Ma, Taejeong Song, Coen A. Ottenheijm, Hyun S. Hwang, Henry M. Gong, Maria Papadaki, Bjorn C. Knollmann, Sakthivel Sadayappan, Thomas C. Irving, Prescott B. Chase, J. Renato Pinto
BIOPHYSICAL JOURNAL
(2022)
Meeting Abstract
Biophysics
Isabella Leite Coscarella, Lili Wang, Jerome Irianto, Bjorn C. Knollmann, Prescott B. Chase, J. Renato Pinto
BIOPHYSICAL JOURNAL
(2022)
Meeting Abstract
Biophysics
Michelle C. Rodriguez Garcia, Maicon Landim-Vieira, Jeffrey Schmeckpeper, Lili Wang, Moore B. Shoemaker, Prescott B. Chase, Bjorn C. Knollmann, J. Renato Pinto
BIOPHYSICAL JOURNAL
(2022)