Review
Neurosciences
Beata Monfort, Kristian Want, Sylvain Gervason, Benoit D'Autreaux
Summary: Friedreich's ataxia (FRDA) is a prevalent autosomic recessive ataxia that is associated with severe cardiac hypertrophy and less commonly, diabetes. It is caused by mutations in the gene encoding frataxin, a mitochondrial protein involved in iron metabolism. Recent discoveries suggest that frataxin functions as an accelerator in the biosynthesis of Fe-S clusters, which may have implications for the development of therapeutic treatments for FRDA.
FRONTIERS IN NEUROSCIENCE
(2022)
Review
Biochemistry & Molecular Biology
Savina Apolloni, Martina Milani, Nadia D'Ambrosi
Summary: Friedreich's ataxia (FRDA) is a rare genetic disorder caused by mutations in the frataxin gene, leading to progressive nervous system damage. In addition to neurons, alterations in glial cells and neuroinflammatory-related mechanisms may contribute to the pathogenesis of FRDA.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Clinical Neurology
Gilbert Thomas-Black, Daniel R. Altmann, Harry Crook, Nita Solanky, Ferran Prados Carrasco, Marco Battiston, Francesco Grussu, Marios C. Yiannakas, Baris Kanber, Jasleen K. Jolly, Jon Brett, Susan M. Downes, Marni Moran, Ping K. Chan, Emmanuel Adewunmi, Claudia A. M. Gandini Wheeler-Kingshott, Andrea H. Nemeth, Richard Festenstein, Fion Bremner, Paola Giunti
Summary: This study comprehensively evaluated the degeneration of the retina in FRDA patients and found heterogeneity in different retinal sectors. The thickness of the retinal nerve fiber layer was associated with frataxin levels. These findings have implications for future clinical trial design.
MOVEMENT DISORDERS
(2023)
Review
Pharmacology & Pharmacy
Wenyao Yang, Bruce Thompson, Faith A. A. Kwa
Summary: Friedreich's ataxia is caused by an intronic GAA trinucleotide expansion in the gene, leading to frataxin protein deficiency. Current management focuses on symptomatic relief as there are no treatments to prevent disease progression, highlighting the importance of targeting molecular pathways to alter the course of the condition.
DRUG DISCOVERY TODAY
(2022)
Article
Biochemistry & Molecular Biology
Mauro Marengo, Alex Fissore, Simonetta Oliaro-Bosso, Salvatore Adinolfi, Annalisa Pastore
Summary: This study proposes a new approach for studying iron-sulfur cluster biogenesis using genetically engineered bacterial strains and metabolomics. The ex vivo method closely reproduces the in vitro results while retaining the complexity of the system.
Article
Cell Biology
Simge Kelekci, Abdullah Burak Yildiz, Kenan Sevinc, Deniz Ugurlu Cimen, Tamer Onder
Summary: This article discusses the current status and challenges of research on Friedreich's ataxia, with a focus on the application of animal models, patient-derived materials, and induced pluripotent stem cell models. The article explores the investigation of disease mechanisms and potential therapeutic agents for Friedreich's ataxia using these models.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Jing Du, Zhaoyang Huang, Yanchun Li, Xueying Ren, Chaoting Zhou, Ruolan Liu, Ping Zhang, Guojie Lei, Jianxin Lyu, Jianghui Li, Guoqiang Tan
Summary: Copper is a necessary mineral nutrient but excess copper is cytotoxic. Wilson's disease is an autosomal recessive hereditary disease characterized by pathological copper accumulation in organs. The molecular mechanism of Wilson's disease is not fully understood and further research is needed to develop therapeutic strategies.
FREE RADICAL BIOLOGY AND MEDICINE
(2023)
Article
Neurosciences
Elisabetta Indelicato, Klaus Faserl, Matthias Amprosi, Wolfgang Nachbauer, Rainer Schneider, Julia Wanschitz, Bettina Sarg, Sylvia Boesch
Summary: This study used proteomics analysis to compare muscle samples from FRDA patients and controls, and found significant differences in mitochondrial protein profiles and metabolic pathways. These findings have important implications for the design of future therapeutic strategies.
FRONTIERS IN NEUROSCIENCE
(2023)
Article
Multidisciplinary Sciences
Oscar A. Campos, Narsis Attar, Chen Cheng, Maria Vogelauer, Nathan Mallipeddi, Stefan Schmollinger, Nedas Matulionis, Heather R. Christofk, Sabeeha S. Merchant, Siavash K. Kurdistani
Summary: This study reveals that histone H3-mediated Cu1+ toxicity is a major determinant of cellular functional pool of Fe-S clusters. Inadequate Fe-S cluster supply causes severe metabolic and growth defects. Decreasing Cu1+ abundance restores Fe-S cluster-dependent metabolism and growth.
Article
Biochemistry & Molecular Biology
Lucia D. Espeche, Karl Ellioth Sewell, Ignacio H. Castro, Luciana Capece, Maria Florencia Pignataro, Liliana Dain, Javier Santos
Summary: The study found that replacement of frataxin by glycine at different tryptophan sites resulted in varying effects on iron-sulfur cluster assembly activity, with W155G showing no activity, W168G being fully active, and W173G having significantly decreased activity. Additionally, W173G may exhibit altered motions at the Trp155 site.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2022)
Article
Biochemistry & Molecular Biology
Suran Nethisinghe, Maheswaran Kesavan, Heather Ging, Robyn Labrum, James M. Polke, Saiful Islam, Hector Garcia-Moreno, Martina F. Callaghan, Francesca Cavalcanti, Mark A. Pook, Paola Giunti
Summary: Studies have shown that small interruptions at the 3' end of the GAA repeat tract are more common in FRDA patients, with 3' interruptions being the most frequent. Patients with 3' interruptions are associated with shorter GAA1 repeat tracts and later ages at disease onset. Model predictions suggest that a 3' interruption may delay disease onset by approximately 9 years compared to patients lacking interruptions. This highlights the significant impact of 3' interruptions on modulating the disease phenotype and prognosis for the patient.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Wing-Hang Tong, Hayden Ollivierre, Audrey Noguchi, Manik C. Ghosh, Danielle A. Springer, Tracey A. Rouault
Summary: Cardiomyopathy is a primary cause of death in Friedreich ataxia patients with defective iron-sulfur cluster biogenesis. The mTOR and AKT signaling cascades play crucial roles in regulating cardiovascular growth and homeostasis, with mTOR and AKT hyperactivations possibly as part of the metabolic stress response to ISC deficiencies.
Article
Biology
Ganeko Bernardo-Seisdedos, Andreas Schedlbauer, Tania Pereira-Ortuzar, Jose M. Mato, Oscar Millet
Summary: In this study, it was demonstrated that human frataxin can bind to zinc in a structurally similar way to iron, but with lower affinity. In addition, both iron-loaded and zinc-loaded frataxins specifically associate with protoporphyrin IX. These findings expand the understanding of frataxin's molecular targets and provide insights into its unknown roles in iron regulation and metabolism.
Article
Cell Biology
Arthavan Selvanathan, Bindu Parayil Sankaran
Summary: Iron-sulfur clusters (ISCs) are highly conserved moieties found in crucial proteins in bacteria, plants and mammals, with defects in the ISC pathway being associated with various human disease states. These disorders often involve neurological phenotypes and share common biochemical features. Therapies are primarily supportive, but improved understanding of the pathophysiology may lead to disease-modifying therapies in the future.
Review
Microscopy
Tiara V. Hinton, Sharon Batelu, Noah Gleason, Timothy L. Stemmler
Summary: Fe-S clusters play crucial roles in biochemical pathways in living organisms, synthesizing through mitochondrial and cytosolic pathways in eukaryotes. Deficiency in Fe-S clusters can be detrimental to cell and organism viability.
Article
Chemistry, Multidisciplinary
Cheng-Wei Lin, Jacob W. McCabe, David H. Russell, David P. Barondeau
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2020)
Article
Genetics & Heredity
Susan E. Tsutakawa, Chi-Lin Tsai, Chunli Yan, Amer Bralic, Walter J. Chazin, Samir M. Hamdan, Orlando D. Scharer, Ivaylo Ivanov, John A. Tainer
Article
Biochemistry & Molecular Biology
Eric J. Tomko, Olivia Luyties, Jenna K. Rimel, Chi-Lin Tsai, Jill O. Fuss, James Fishburn, Steven Hahn, Susan E. Tsutakawa, Dylan J. Taatjes, Eric A. Galburt
Summary: The general transcription factor TFIIH contains three ATP-dependent catalytic activities and functions in nucleotide excision repair and Pol II transcription initiation. While the functions are conserved between metazoans and yeast, yeast TFIIH drives transcription start-site scanning. Human and yeast core-TFIIH complexes lack processive translocation, with the yeast kinase module aiding in robust transcription start-site scanning.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Chemistry, Analytical
Jacob W. McCabe, Mehdi Shirzadeh, Thomas E. Walker, Cheng-Wei Lin, Benjamin J. Jones, Vicki H. Wysocki, David P. Barondeau, David E. Clemmer, Arthur Laganowsky, David H. Russell
Summary: The stability and structure of proteins are influenced by various factors in their local environment, and a new variable-temperature electrospray ionization (vT-ESI) source has been developed to study the effects of temperature on protein folding and ligand binding. This apparatus allows for rapid and precise control of solution temperature changes, enabling research on temperature-dependent protein reactions with high efficiency.
ANALYTICAL CHEMISTRY
(2021)
Article
Biology
Hou-Fu Guo, Neus Bota-Rabassedas, Masahiko Terajima, B. Leticia Rodriguez, Don L. Gibbons, Yulong Chen, Priyam Banerjee, Chi-Lin Tsai, Xiaochao Tan, Xin Liu, Jiang Yu, Michal Tokmina-Roszyk, Roma Stawikowska, Gregg B. Fields, Mitchell D. Miller, Xiaoyan Wang, Juhoon Lee, Kevin N. Dalby, Chad J. Creighton, George N. Phillips, John A. Tainer, Mitsuo Yamauchi, Jonathan M. Kurie
Summary: Guo et al. have determined the molecular basis of collagen lysyl hydroxylase 2 (LH2) substrate specificity, showing that LH2 functions not only as a telopeptidyl lysyl hydroxylase, but also as a collagen glucosyltransferase to drive lung cancer progression. The research suggests that LH2 plays a crucial role in promoting LUAD progression through a variety of mechanisms, including tLH-dependent and tLH-independent pathways.
COMMUNICATIONS BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Zu Ye, Shengfeng Xu, Yin Shi, Albino Bacolla, Aleem Syed, Davide Moiani, Chi-Lin Tsai, Qiang Shen, Guang Peng, Paul G. Leonard, Darin E. Jones, Bin Wang, John A. Tainer, Zamal Ahmed
Summary: In this study, GRB2 was found to play a crucial role in DNA double-strand break repair by forming a complex with MRE11 to promote efficient homology-directed repair initiation and releasing MRE11 through ubiquitination. Depletion of RBBP6 leads to prolonged HDR defects, highlighting GRB2's importance in the repair process.
Article
Multidisciplinary Sciences
Jianxin Liu, Jiayi Tian, Christopher Perry, April L. Lukowski, Tzanko Doukov, Alison R. H. Narayan, Jennifer Bridwell-Rabb
Summary: In this study, the crystal structures of two Rieske oxygenases, SxtT and GxtA, were determined with their native substrates. The authors also identified key amino acid residues that determine the substrate specificity and site selectivity of these enzymes. These findings provide valuable insights for the engineering of Rieske oxygenases.
NATURE COMMUNICATIONS
(2022)
Article
Biology
Bin Li, Minshik Jo, Jianxin Liu, Jiayi Tian, Robert Canfield, Jennifer Bridwell-Rabb
Summary: The DNA binding and H2O2 sensing mechanisms of a transcriptional regulator called RexT found in cyanobacteria have been revealed. RexT uses disulfide bond formation as a trigger to bind and release DNA and has a winged-helix-turn-helix fold to respond to H2O2. The study also identifies the entrance channel for H2O2 and key residues involved in H2O2 activation. Additionally, it is discovered that the vicinal disulfide redox switch is a unique feature of cyanobacteria in the Nostocales order.
COMMUNICATIONS BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Mihyun Kim, Hyun-Suk Kim, Areetha D'Souza, Kaitlyn Gallagher, Eunwoo Jeong, Kateryna Ogorodnik Le Meur, Chi-Lin Tsai, Miaw-Sheue Tsai, Minyong Kee, John A. Tainer, Jung-Eun Yeo, Walter J. Chazin, Orlando D. Scharer
Summary: The XPA and RPA proteins play essential roles in the assembly of the preincision complex in the nucleotide excision repair pathway. Mutations in the interaction sites of XPA and RPA inhibit the physical interaction and reduce the NER activity. The interaction between XPA-N and RPA32C is important for the initial association of XPA with NER complexes, while the interaction between XPA DBD and RPA70AB is needed for structural organization of the complex to license the dual incision reaction. The shape of the NER bubble is not colinear as previously thought, but rather the unwound DNA assumes a U-shape with the junctions localized in close proximity. The interaction between XPA and RPA70 is key for the organization of the NER preincision complex.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Chemistry, Multidisciplinary
Jianxin Liu, Madison Knapp, Minshik Jo, Zerick Dill, Jennifer Bridwell-Rabb
Summary: Rieske oxygenases play a crucial role in anabolic and catabolic pathways by performing precise C-H bond functionalization reactions. This study demonstrated that CAO can convert chlorophyllida into chlorophyllideb in vitro, highlighting its potential as a tool for synthesizing custom-tuned chlorophyll pigments.
ACS CENTRAL SCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Cheng-Wei Lin, Shelby D. Oney-Hawthorne, Syuan-Ting Kuo, David P. Barondeau, David H. Russell
Summary: Iron-sulfur (Fe-S) cluster (ISC) cofactors are essential for many cellular processes. IscU plays a key role in the ISC Fe-S cluster biosynthetic pathway and exists in multiple conformational states. Zn binding affects the conformation of IscU and its interaction with IscS. This study provides a structural rationale for the role of Zn in stabilizing IscU conformations and IscS in preparing for cluster synthesis.
Review
Biochemistry & Molecular Biology
Marley Brimberry, Alejandro Arcadio Garcia, Jianxin Liu, Jiayi Tian, Jennifer Bridwell-Rabb
Summary: Enzyme engineering is crucial for various applications, including biotechnology, chemical manufacturing, pharmaceuticals, and environmental remediation. Traditionally, protein design focused on active site residues for desired catalytic properties, but recent studies show that structural elements beyond the active site, like subunit-subunit interactions and flexible loops, also impact enzyme catalysis. This is particularly true for Rieske oxygenases, where the architectural features inside and outside the active site play a significant role in catalysis. Therefore, future Rieske oxygenase engineering efforts should consider these features.
CURRENT OPINION IN CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Saman Fatima, David G. Boggs, Noor Ali, Peter J. Thompson, Megan C. Thielges, Jennifer Bridwell-Rabb, Lisa Olshansky
Summary: In this study, we developed conformationally switchable artificial metalloproteins (swArMs) to better model the natural mechanisms of metalloprotein reactivity. These swArMs undergo a large-scale structural rearrangement upon allosteric effector binding. The site-specific and stoichiometric installation of metallocofactors within the protein fold was confirmed using various spectroscopic and structural characterization methods. This research provides a robust platform for investigating the interplay between allostery and metallocofactor regulation.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Jiayi Tian, Alejandro Arcadio Garcia, Patrick H. Donnan, Jennifer Bridwell-Rabb
Summary: Rieske nonheme iron oxygenases utilize two metallocenters to catalyze oxidation reactions on various substrates. Understanding the structure-function relationships in this enzyme class is crucial for rational redesign and optimization of these enzymes. In this study, by using available structural information and protein modeling tools, the researchers successfully engineered the Rieske oxygenase TsaM to behave as different monooxygenases and expand its substrate range.
Article
Multidisciplinary Sciences
Jiayi Tian, Jianxin Liu, Madison Knapp, Patrick H. Donnan, David G. Boggs, Jennifer Bridwell-Rabb
Summary: By combining structural analyses, substrate and rational protein-based engineering, this study elucidates the architectural trends that govern catalytic outcome in the Rieske monooxygenase TsaM and provides strategies to custom tune Rieske oxygenase reaction outcomes.
NATURE COMMUNICATIONS
(2023)