Article
Chemistry, Multidisciplinary
Nam Gu Yoon, Hakbong Lee, So-Yeon Kim, Sung Hu, Darong Kim, Sujae Yang, Ki Bum Hong, Ji Hoon Lee, Soosung Kang, Byung-Gyu Kim, Kyungjae Myung, Changwook Lee, Byoung Heon Kang
Summary: The study identified Mitoquinone (MitoQ) as a potent inhibitor of mitochondrial Hsp90, offering potential anticancer properties. By competitively binding with TRAP1 clients, MitoQ facilitated the identification of mitochondrial protein interactions. Targeting the client binding site of Hsp90 family proteins provides a novel strategy for developing potent anticancer drugs.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Lena Kraemer, Niko Dalheimer, Markus Raeschle, Zuzana Storchova, Jan Pielage, Felix Boos, Johannes M. Herrmann
Summary: The cytosol can transiently store mitochondrial precursor proteins in dedicated deposits called MitoStores, which suppress the toxic potential of accumulating precursor proteins and are controlled by Hsp42 and Hsp104.
Article
Biology
Layla Drwesh, Benjamin Heim, Max Graf, Linda Kehr, Lea Hansen-Palmus, Mirita Franz-Wachtel, Boris Macek, Hubert Kalbacher, Johannes Buchner, Doron Rapaport
Summary: This study reconstituted the early cytosolic steps of signal-anchored (SA) protein biogenesis and identified molecular (co)chaperones, including Hsp70, Hsp90, and Hsp40 family co-chaperones, that interact with newly synthesized SA proteins. These interactions are mediated by the hydrophobic transmembrane segments of the SA proteins. The study also demonstrated the inhibitory effect of interfering with these interactions on SA protein biogenesis and successfully reconstituted the transfer of peptides from Hsp70 chaperone to the mitochondrial Tom70 receptor in vitro.
Article
Multidisciplinary Sciences
Zhiqiang Hou, Pawel M. Wydorski, Valerie A. Perez, Ayde Mendoza-Oliva, Bryan D. Ryder, Hilda Mirbaha, Omar Kashmer, Lukasz A. Joachimiak
Summary: The study reveals that DnaJC7 preferentially binds to natively folded wild-type tau, while reducing affinity to aggregation-prone tau mutants. This preference may serve as a novel mechanism for regulating tau aggregation and potential diagnostic and therapeutic interventions.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Nicolas Bloemeke, Kevin Meighen-Berger, Manuel Hitzenberger, Nina C. Bach, Marina Parr, Joao Pl Coelho, Dmitrij Frishman, Martin Zacharias, Stephan A. Sieber, Matthias J. Feige
Summary: One-third of the human proteome is composed of membrane proteins, which are susceptible to misfolding and require folding assistance from chaperones. Calnexin, an abundant ER chaperone, interacts with a large number of membrane proteins, including misfolded ones, using its lectin domain and transmembrane domain for recognition and binding. This study reveals the widespread role of calnexin in recognizing client proteins in the lipid bilayer and highlights its importance in supporting membrane protein biogenesis.
Review
Biochemistry & Molecular Biology
J. J. Ruprecht, E. R. S. Kunji
Summary: Members of the mitochondrial carrier family transport a variety of molecules across the mitochondrial inner membrane, playing crucial roles in cellular processes. The transport mechanism involves a central substrate-binding site, gates with salt-bridge networks, and conformational changes triggered by substrate binding during import and export.
ANNUAL REVIEW OF BIOCHEMISTRY, VOL 90, 2021
(2021)
Article
Biochemistry & Molecular Biology
Filipe E. P. Rodrigues, Antonio J. Figueira, Claudio M. Gomes, Miguel Machuqueiro
Summary: Computational analysis revealed that Aβ-Lys28 plays a key role in stabilizing interactions with S100B, involving residues such as Met79, Thr82, and Glu86. Coulombic interactions, potentially involving the Lys28(Aβ)/Glu86(S100B) pair, are crucial for the holdase-type chaperone activity of S100B, and high ionic strength can reduce the anti-aggregation activity of the Aβ-S100B interaction through electrostatic perturbation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Lingfeng Chen, Lili Fu, Jingchuan Sun, Zhiqiang Huang, Mingzhen Fang, Allen Zinkle, Xin Liu, Junliang Lu, Zixiang Pan, Yang Wang, Guang Liang, Xiaokun Li, Gaozhi Chen, Moosa Mohammadi
Summary: This study reveals the molecular mechanism and asymmetric receptor dimerization mode of the FGF23-FGFR-alpha Klotho-HS quaternary complexes, overturning the current symmetric FGFR dimerization paradigm. It also provides blueprints for the discovery of therapeutic targets for human metabolic diseases and cancer.
Article
Cell Biology
Peristera Roboti, Craig Lawless, Stephen High
Summary: The heterotrimeric BAG6 complex plays a role in coordinating the transport of newly synthesised membrane proteins and processing defective precursors. It also interacts with the mitochondrial antiviral-signalling protein MAVS and regulates its role in the cellular response to viral infection.
JOURNAL OF CELL SCIENCE
(2022)
Article
Multidisciplinary Sciences
Corvin Walter, Adinarayana Marada, Tamara Suhm, Ralf Ernsberger, Vera Muders, Cansu Kuecuekkoese, Pablo Sanchez-Martin, Zehan Hu, Abhishek Aich, Stefan Loroch, Fiorella Andrea Solari, Daniel Poveda-Huertes, Alexandra Schwierzok, Henrike Pommerening, Stanka Matic, Jan Brix, Albert Sickmann, Claudine Kraft, Joern Dengjel, Sven Dennerlein, Tilman Brummer, F. -Nora Voegtle, Chris Meisinger
Summary: The study shows that DYRK1A phosphorylates TOM70 to promote import of precursor proteins into mitochondria. Inhibition of DYRK1A impairs mitochondrial structure and function, leading to a decrease in metabolite carrier import capacity.
NATURE COMMUNICATIONS
(2021)
Review
Biochemistry & Molecular Biology
Francoise A. Dekker, Stefan G. D. Rudiger
Summary: This article discusses the molecular mechanism and cellular function of TRAP1, and explores possible links to Alzheimer's Disease (AD). TRAP1, as a member of the Hsp90 family, plays a crucial role in chaperoning essential cellular proteins despite not being regulated by co-chaperones like its cytosolic counterparts. It is also involved in maintaining mitochondrial integrity by regulating mitochondrial pore opening through Cyclophilin D.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Multidisciplinary Sciences
Yuzuru Itoh, Juni Andrell, Austin Choi, Uwe Richter, Priyanka Maiti, Robert B. Best, Antoni Barrientos, Brendan J. Battersby, Alexey Amunts
Summary: The study reveals the mechanism of interaction between human mitoribosomes and the insertase OXA1L, elucidating how membrane delivery is achieved during protein synthesis.
Review
Biochemistry & Molecular Biology
Jakob D. Busch, Laura F. Fielden, Nikolaus Pfanner, Nils Wiedemann
Summary: Biogenesis of mitochondria involves the import of numerous precursor proteins across the mitochondrial membranes. Different import pathways exist, ranging from presequence-directed pathway to pathways using internal or carboxy-terminal targeting signals. Recent studies have revealed the structural organization of membrane-embedded preprotein translocases and their dynamic interactions with other cellular machineries. These insights provide valuable knowledge about the mechanisms of mitochondrial protein import.
Article
Biochemistry & Molecular Biology
Angelica Zamudio-Ochoa, Yaroslav Morozov, Azadeh Sarfallah, Michael Anikin, Dmitry Temiakov
Summary: Recognition of mammalian mitochondrial promoters is achieved through the concerted action of mitochondrial RNA polymerase (mtRNAP) and transcription initiation factors TFAM and TFB2M. This study provides insights into the heterogeneity of mitochondrial transcripts and accurately identifies the transcription start sites (TSS) of mammalian and other vertebrate species. The divergent structure of mammalian promoters reveals new aspects of mtDNA evolution and the precise register of the DNA in the initiation complex. The findings also shed light on the molecular basis of promoter recognition and the role of mitochondrial transcription machinery in mitonuclear coevolution and speciation.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Multidisciplinary Sciences
Amrita Rai, Anurag K. Singh, Nathalie Bleimling, Guido Posern, Ingrid R. Vetter, Roger S. Goody
Summary: Rep15 is an effector that interacts with the GTPase Rab15. Here, the authors show that Rep15 also interacts with Rab3 paralogs and Rab34, present crystal structures of Rep15:Rab complexes and find that Rep15 depletion in glioblastoma cells decreases proliferation and mobility.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Lea Marie Becker, Melanie Berbon, Alicia Vallet, Axelle Grelard, Estelle Morvan, Benjamin Bardiaux, Roman Lichtenecker, Matthias Ernst, Antoine Loquet, Paul Schanda
Summary: Aromatic side chains play a significant role in protein plasticity and protein-protein interactions. Through isotope-labeling and NMR techniques, we studied the behavior of aromatic residues in two structurally homologous amyloid fibrils. We found that the hydrophobic amyloid core is rigid, while aromatic residues on the fibril surface undergo ring flips. This insight provides a better understanding of the conformational heterogeneity in amyloid cross-beta architecture.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
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
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)
Article
Multidisciplinary Sciences
Morris Degen, Jose Carlos Santos, Kristyna Pluhackova, Gonzalo Cebrero, Saray Ramos, Gytis Jankevicius, Ella Hartenian, Undina Guillerm, Stefania A. Mari, Bastian Kohl, Daniel J. Mueller, Paul Schanda, Timm Maier, Camilo Perez, Christian Sieben, Petr Broz, Sebastian Hiller
Summary: Eukaryotic cells can undergo different forms of programmed cell death, many of which culminate in plasma membrane rupture. The protein ninjurin-1 (NINJ1) mediates the active process of membrane rupture in dying cells. NINJ1 clusters into structurally diverse assemblies in dying cell membranes, particularly large filamentous assemblies with branched morphology. Molecular dynamics simulations show that NINJ1 can stably cap membrane edges. Therefore, NINJ1 is an interactive component of the eukaryotic cell membrane that functions as an in-built breaking point in response to activation of cell death.
Article
Multidisciplinary Sciences
Yunyun Wang, Zhenni Li, Xinyu Wang, Ziyuan Zhao, Li Jiao, Ruming Liu, Keying Wang, Rui Ma, Yang Yang, Guo Chen, Yong Wang, Xin Bian
Summary: This study investigates the molecular basis of membrane association by the SMP domain of extended synaptotagmin (E-Syt) through in vitro DNA brick-assisted lipid transfer assays and molecular dynamics simulations. The results show that the SMP domain recognizes the highly curved subdomain of the tubular ER and the acidic-lipid-enriched plasma membrane for efficient lipid transfer. These findings support a model for the action of the SMP domain at membrane contact sites (MCSs).
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Physical
Bin Ji, Jianxiang Huang, Kexuan Zou, Meijun Liu, Yufeng Pei, Jing Huang, Yong Wang, Jinglin Wang, Ruhong Zhou, Wenwen Xin, Jie Song
Summary: This study provides theoretical and experimental evidence of the pre-pore morphology of Clostridium perfringens epsilon toxin (ETX) using in situ atomic force microscopy (AFM) and molecular dynamics (MD) simulations. The results show that the ETX pore is formed in two stages: ETX monomers first attach to the membrane and form a pre-pore, which then undergoes a conformational change to form a transmembrane pore in the presence of receptors at temperatures above the critical point. The study also reveals that initial nucleation occurs when specific amino acids adsorb to negatively charged mica cavities. This research fills the knowledge gap in understanding the early stage of hemolysis and the oligomerization of hemolysins, and the ETX pre-pore shows potential for nanopore applications.
Article
Biology
Ying Huang, Chenyang Xue, Liangdong Wang, Ruiqian Bu, Jianqiang Mu, Yong Wang, Zhongmin Liu
Summary: This study uses cryo-EM to resolve the structures of hMRP4 in different states, including apo inward-open, ATP-bound outward-open, PGE1 substrate-bound, and sulindac inhibitor-bound states. The findings reveal the competition between substrate and inhibitor for the same binding pocket and provide insights into the transport and inhibition mechanism of hMRP4, which have implications for drug development.
COMMUNICATIONS BIOLOGY
(2023)
Review
Plant Sciences
Tobias Jores, Morgan Hamm, Josh T. Cuperus, Christine Queitsch
Summary: Understanding plant gene regulation has been a long-standing challenge for plant scientists. Recent advancements in next-generation sequencing technology and computational approaches have provided new insights into the regulatory code of plants. This review discusses these methods and their contribution to our understanding of plant gene regulation.
CURRENT OPINION IN PLANT BIOLOGY
(2023)
Article
Chemistry, Physical
Iva Sucec, Nadia El Mammeri, Aurelio J. Dregni, Mei Hong
Summary: Single-span oligomeric & alpha;-helical transmembrane proteins are common targets of antiviral drugs, but their high-resolution structures are not well understood. This study introduces a simple solid-state NMR approach using magnetization transfer from water and lipid protons to accelerate the experimental structure determination of these proteins. Results demonstrate successful application of this approach on the envelope protein of SARS-CoV-2, revealing the topology of the helical bundles. The experiments also show interesting differences in the positions of aromatic residues in the envelope proteins of different coronaviruses.
JOURNAL OF PHYSICAL CHEMISTRY B
(2023)
Article
Multidisciplinary Sciences
Haidai Hu, Philipp F. Popp, Monica Santiveri, Aritz Roa-Eguiara, Yumeng Yan, Freddie J. O. Martin, Zheyi Liu, Navish Wadhwa, Yong Wang, Marc Erhardt, Nicholas M. I. Taylor
Summary: In this study, the structure of Vibrio PomAB was determined by cryo-electron microscopy, revealing sodium binding sites, and a mechanism for ion translocation and selectivity was proposed through functional experiments and molecular dynamics simulations. The involvement of a dynamic helical motif in PomA was suggested to regulate the distance between PomA subunit cytoplasmic domains, stator unit activation, and torque transmission. Overall, this study provides mechanistic insights into ion selectivity and rotor incorporation of the stator unit of the bacterial flagellum.
NATURE COMMUNICATIONS
(2023)