Article
Biochemistry & Molecular Biology
Luca Sesta, Guido Uguzzoni, Jorge Fernandez-de-Cossio-Diaz, Andrea Pagnani
Summary: AMaLa is a new method for inferring fitness landscapes from Directed Evolution experiments sequencing data, effectively leveraging the information encoded in the entire time evolution and using a time-dependent statistical weight with two contributions to gauge possible trajectories in sequence space. This approach accurately describes Directed Evolution dynamics and infers a fitness landscape that reproduces measures of the phenotype under selection, outperforming widely used inference strategies. The reliability of AMaLa is assessed by demonstrating how the inferred statistical model can predict relevant structural properties of the wild-type sequence.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Ido Caspy, Mariia Fadeeva, Sebastian Kuhlgert, Anna Borovikova-Sheinker, Daniel Klaiman, Gal Masrati, Friedel Drepper, Nir Ben-Tal, Michael Hippler, Nathan Nelson
Summary: Photosystem I is defined as plastocyanin-ferredoxin oxidoreductase, and the study using genetic engineering, kinetic analyses and cryo-EM provides novel insights into the binding and electron transfer between PSI and Pc. The structural data at 2.74 angstrom resolution reveals strong hydrophobic interactions in the plant PSI-Pc ternary complex, leading to exclusion of water molecules from PsaA-PsaB/Pc interface once the PSI-Pc complex forms. Upon oxidation of Pc, a slight tilt of bound oxidized Pc allows water molecules to accommodate the space between Pc and PSI to drive Pc dissociation, explaining the optimized electron transfer for fast turnover in this molecular machine.
BIOCHEMICAL JOURNAL
(2021)
Article
Chemistry, Physical
Thomas Blum, Jeffery Graves, Michael J. Zachman, Felipe Polo-Garzon, Zili Wu, Ramakrishnan Kannan, Xiaoqing Pan, Miaofang Chi
Summary: Forming an ultra-thin, permeable encapsulation oxide-support layer on a metal catalyst surface is considered an effective strategy for achieving a balance between high stability and high activity in heterogenous catalysts, but identifying such a trace layer has been challenging. A new robust, unsupervised machine learning data analysis method has been developed to accurately reveal trace encapsulation layers in STEM-EELS datasets that are otherwise overlooked, providing a reliable tool for analyzing catalyst encapsulation.
Article
Virology
Yuan Li, Sarah Arcos, Kimberly R. Sabsay, Aartjan J. W. te Velthuis, Adam S. Lauring
Summary: The influenza virus polymerase plays a central role in the evolution of the virus. Mutations in the polymerase are necessary for the efficient spread of animal-derived viruses in human populations. The polymerase also determines the rate at which the virus acquires mutations that lead to drug resistance or antigenic drift. However, our understanding of the effects of mutations on the influenza RNA-dependent RNA polymerase (RdRp) is limited. In this study, deep mutational scanning of a specific protein in the polymerase was performed to understand the constraints and effects of mutations. The results provide valuable insights into the replication and evolution of the influenza virus.
JOURNAL OF VIROLOGY
(2023)
Article
Engineering, Biomedical
Tie Liang, Lei Hong, Jinzhuang Xiao, Lixin Wei, Xiaoguang Liu, Hongrui Wang, Bin Dong, Xiuling Liu
Summary: This study aims to analyze the changes in cortical and muscle connections in healthy subjects during different standing balance tasks. The results show significant changes in the topology of both EEG brain networks and muscle networks as the task difficulty increases. The connection analysis of muscle networks reveals that antagonistic muscle pairs play a major role in the task. The analysis of EEG brain networks based on graph theory shows a significant increase in clustering coefficient and a significant decrease in characteristic path length with increasing task difficulty. It is also found that cortex-to-muscle connections increase with task difficulty and are significantly stronger than muscle-to-cortex connections.
JOURNAL OF NEURAL ENGINEERING
(2022)
Article
Biochemistry & Molecular Biology
Qingdan Du, Yen-Hua Huang, Conan K. Wang, Quentin Kaas, David J. Craik
Summary: Cyclotides are a family of macrocyclic peptides with diverse bioactivities. Understanding the role of individual residues in their structure and function has been challenging, particularly for the bracelet subfamily. This study investigated the role of specific residues in bracelet cyclotides through mutagenesis, revealing their importance in maintaining structure, membrane binding, and cytotoxic activity. These findings provide valuable insights for future biotechnological applications of bracelet cyclotides.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Roa'a Jaradat, Xiaole Li, Honghong Chen, Peter B. Stathopulos, Donglin Bai
Summary: Functional studies and structural models of Cx46 and Cx50 GJs reveal the importance of hydrophobic interactions between the NT and TM2 domains in V-j-gating, gamma(j), and channel open stability.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Matteo Busato, Giorgia Mannucci, Valerio Di Lisio, Andrea Martinelli, Alessandra Del Giudice, Alessandro Tofoni, Chiara Dal Bosco, Valentina Migliorati, Alessandra Gentili, Paola D'Angelo
Summary: An integrated approach combining various techniques was used to study the hydrophobic eutectic solvent formed by BHT and MEN. The study showed that the hydroxyl group of BHT has little impact on the thermal behavior of the eutectic. No hydrogen bond interactions were observed for BHT due to steric hindrance, while strong hydrogen bonds were formed between MEN molecules. The three-dimensional arrangement of the components indicated a high degree of structural order, suggesting that apolar-apolar attraction is the driving force of eutectic formation.
ACS SUSTAINABLE CHEMISTRY & ENGINEERING
(2022)
Article
Biochemistry & Molecular Biology
Laura Perna, Matteo Castelli, Elena Frasnetti, Lisa E. L. Romano, Giorgio Colombo, Chrisostomos Prodromou, J. Paul Chapple
Summary: In this study, an AlphaFold structure of sacsin was compared with yeast Hsp90, revealing novel insights into the structure of sacsin. Residues within sacsin's Hsp90-like domains required for ATP binding and hydrolysis were identified, including catalytic arginine residues equivalent to Hsp90's middle domain. This study supports the hypothesis that sacsin functions as an ATP-driven super molecular chaperone.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Brandon A. Keith, John C. S. Harding, Matthew E. Loewen
Summary: Oligomeric assembly and hemolytic activity of TlyA from Brachyspira hampsonii depend on the formation of an intermolecular C80-C80 disulfide bond and noncovalent interactions involving serine 9. A conserved mutation (S9K) in TlyA protein can completely abolish its hemolytic activity.
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
(2022)
Article
Biochemistry & Molecular Biology
Tomoya Komatsu, Ikuo Matsui, Hideshi Yokoyama
Summary: This study reveals the important role of stomatin in human erythrocytes and provides insights into its molecular function and oligomerization state.
BIOCHEMISTRY AND BIOPHYSICS REPORTS
(2022)
Article
Microbiology
Nathaniel D. M. Holman, Anthony J. Wilkinson, Margaret C. M. Smith
Summary: In this study, the structure and function of S. coelicolor Pmt were investigated by mutating highly conserved residues. The results showed that substitutions of certain conserved residues led to loss of Pmt function, highlighting the importance of residue conservation for enzyme activity.
Article
Biology
J. Ignacio Gutierrez, Gregory P. Brittingham, Yonca Karadeniz, Kathleen D. Tran, Arnob Dutta, Alex S. Holehouse, Craig L. Peterson, Liam J. Holt
Summary: It is increasingly recognized that changes in intracellular pH serve as important biological signals. This study focuses on elucidating the molecular mechanisms of pH sensing. The researchers found that a nucleocytoplasmic pH oscillation is crucial for the transcriptional response to carbon starvation in Saccharomyces cerevisiae. They also discovered that the SWI/SNF chromatin remodeling complex plays a key role in this response. Specifically, a glutamine-rich low-complexity domain (QLC) in the SNF5 subunit of this complex, along with histidines within this domain, is essential for efficient transcriptional reprogramming. Additionally, the SNF5 QLC is responsible for the pH-dependent recruitment of SWI/SNF to an acidic transcription factor in a reconstituted nucleosome remodeling assay. Simulations revealed that the protonation of histidines in the SNF5 QLC causes conformational expansion, offering a potential biophysical mechanism for regulating these interactions. Overall, this study suggests that pH changes act as a second messenger for transcriptional reprogramming during carbon starvation, with the SNF5 QLC serving as a pH sensor.
Editorial Material
Biochemistry & Molecular Biology
Garrett M. Ginell, Alex S. Holehouse
Summary: This article investigates the impact of phosphorylation modification on the C-terminal domain of TDP-43, a protein implicated in Amyotrophic Lateral Sclerosis (ALS).
Article
Biochemistry & Molecular Biology
Andrea Soranno, J. Jeremias Incicco, Paolo De Bona, Eric J. Tomko, Eric A. Galburt, Alex S. Holehouse, Roberto Galletto
Summary: Telomere scaffolding protein TRF2 condenses individual DNA chains and drives coalescence of multiple molecules, leading to phase separation and the formation of liquid-like droplets.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Editorial Material
Cell Biology
Ryan J. Emenecker, Alex S. Holehouse
NATURE CELL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Nicolas S. Gonzalez-Foutel, Juliana Glavina, Wade M. Borcherds, Matias Safranchik, Susana Barrera-Vilarmau, Amin Sagar, Alejandro Estana, Amelie Barozet, Nicolas A. Garrone, Gregorio Fernandez-Ballester, Clara Blanes-Mira, Ignacio E. Sanchez, Gonzalo De Prat-Gay, Juan Cortes, Pau Bernado, Rohit Pappu, Alex S. Holehouse, Gary W. Daughdrill, Lucia B. Chemes
Summary: This study identifies the molecular mechanism of functional selection in disordered proteins and highlights the importance of conformational buffering and motif-linker coevolution for functional encoding.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Hongwei Jing, Xiaolu Yang, Ryan J. Emenecker, Jian Feng, Jian Zhang, Marcelo Rodrigues Alves de Figueiredo, Patarasuda Chaisupa, R. Clay Wright, Alex S. Holehouse, Lucia C. Strader, Jianru Zuo
Summary: The plant hormone auxin is involved in various aspects of plant growth and development, and nitric oxide (NO) acts as a negative regulator of auxin signaling by inhibiting the degradation of IAA17 protein. S-nitrosylation of Cys-70 in IAA17 prevents its interaction with TIR1, leading to reduced auxin response. This study provides insights into the molecular mechanisms of redox-based auxin signaling in plant growth and development.
JOURNAL OF GENETICS AND GENOMICS
(2023)
Article
Chemistry, Physical
Jhullian J. J. Alston, Garrett M. M. Ginell, Andrea Soranno, Alex S. S. Holehouse
Summary: Unfolded proteins, including denatured, unfolded, and intrinsically disordered proteins, can be described using analytical polymer models. The analytical Flory random coil (AFRC) model, parameterized using all-atom simulations and polymer scaling theory, provides a simple-to-use reference state for comparing and normalizing experimental or computational results. The AFRC model allows identification of sequence-specific intramolecular interactions and contextualization of radii of gyration from small-angle X-ray scattering experiments of disordered proteins.
JOURNAL OF PHYSICAL CHEMISTRY B
(2023)
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
Biochemistry & Molecular Biology
Brittany A. Townley, Luke Buerer, Ning Tsao, Albino Bacolla, Fadhel Mansoori, Timur Rusanov, Nathanial Clark, Negar Goodarzi, Nicolas Schmidt, Sridhar Nonavinkere Srivatsan, Hua Sun, Reilly A. Sample, Joshua R. Brickner, Drew McDonald, Miaw-Sheue Tsai, Matthew J. Walter, David F. Wozniak, Alex S. Holehouse, Vladimir Pena, John A. Tainer, William G. Fairbrother, Nima Mosammaparast
Summary: This study reveals that intron-processing defects caused by TTDN1/MPLKIP dysfunction contribute to abnormal splicing and gene expression in NP-TTD patient cells. The TTDN1 protein is involved in the binding of lariat debranching enzyme DBR1 and the intron-binding complex (IBC), and its loss or mutation leads to intron lariat accumulation and splicing defects.
Review
Biochemistry & Molecular Biology
David Moses, Garrett M. Ginell, Alex S. Holehouse, Shahar Sukenik
Summary: Intrinsically disordered proteins and protein regions (IDRs) play essential roles in eukaryotic organisms. Unlike folded proteins, IDRs exist in a conformational ensemble influenced by sequence-dependent interactions. The absence of a stable 3D structure and high solvent accessibility make IDRs inherently sensitive to environmental changes, allowing them to act as sensors and actuators of cellular physicochemistry.
TRENDS IN BIOCHEMICAL SCIENCES
(2023)
Article
Biochemical Research Methods
Garrett M. Ginell, Aidan J. Flynn, Alex S. Holehouse
Summary: SHEPHARD is a Python framework that simplifies large-scale integrative protein bioinformatics. It combines an object-oriented hierarchical data structure with database-like features, enabling programmatic annotation, integration, and analysis of complex datatypes. It can be used to examine the relationship between protein sequences and molecular function, uncovering novel biology.
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)
Meeting Abstract
Biophysics
Jacqueline Pelham, Joshua Thomas, Alexander E. Mosier, Morgan L. Rhodes, Alex S. Holehouse, Jennifer M. Hurley
BIOPHYSICAL JOURNAL
(2022)
Meeting Abstract
Biophysics
Nora M. Shamoon, Karina C. Guadalupe, Ryan Emenecker, Alex S. Holehouse, Shahar Sukenik
BIOPHYSICAL JOURNAL
(2022)