TY - JOUR AU - Kengyel, András Miklós AU - Palarz, Philip M AU - Krohn, Jacqueline AU - Marquardt, Anja AU - Greve, Johannes N AU - Heiringhoff, Robin AU - Jörns, Anne AU - Manstein, Dietmar J TI - Motor properties of Myosin 5c are modulated by tropomyosin isoforms and inhibited by pentabromopseudilin JF - FRONTIERS IN PHYSIOLOGY J2 - FRONT PHYSIOL VL - 15 PY - 2024 PG - 13 SN - 1664-042X DO - 10.3389/fphys.2024.1394040 UR - https://m2.mtmt.hu/api/publication/34797930 ID - 34797930 N1 - * Megosztott szerzőség AB - Myosin 5c (Myo5c) is a motor protein that is produced in epithelial and glandular tissues, where it plays an important role in secretory processes. Myo5c is composed of two heavy chains, each containing a generic motor domain, an elongated neck domain consisting of a single α-helix with six IQ motifs, each of which binds to a calmodulin (CaM) or a myosin light chain from the EF-hand protein family, a coiled-coil dimer-forming region and a carboxyl-terminal globular tail domain. Although Myo5c is a low duty cycle motor, when two or more Myo5c-heavy meromyosin (HMM) molecules are linked together, they move processively along actin filaments. We describe the purification and functional characterization of human Myo5c-HMM co-produced either with CaM alone or with CaM and the essential and regulatory light chains Myl6 and Myl12b. We describe the extent to which cofilaments of actin and Tpm1.6, Tpm1.8 or Tpm3.1 alter the maximum actin-activated ATPase and motile activity of the recombinant Myo5c constructs. The small allosteric effector pentabromopseudilin (PBP), which is predicted to bind in a groove close to the actin and nucleotide binding site with a calculated ΔG of -18.44 kcal/mol, inhibits the motor function of Myo5c with a half-maximal concentration of 280 nM. Using immunohistochemical staining, we determined the distribution and exact localization of Myo5c in endothelial and endocrine cells from rat and human tissue. Particular high levels of Myo5c were observed in insulin-producing β-cells located within the pancreatic islets of Langerhans. LA - English DB - MTMT ER - TY - JOUR AU - Halász, Henriett AU - Tárnai, Viktória AU - Matkó, J AU - Nyitrai, Miklós AU - Szabó-Meleg, Edina TI - Cooperation of Various Cytoskeletal Components Orchestrates Intercellular Spread of Mitochondria between B-Lymphoma Cells through Tunnelling Nanotubes JF - CELLS J2 - CELLS-BASEL VL - 13 PY - 2024 IS - 7 PG - 23 SN - 2073-4409 DO - 10.3390/cells13070607 UR - https://m2.mtmt.hu/api/publication/34777718 ID - 34777718 AB - Membrane nanotubes (NTs) are dynamic communication channels connecting spatially separated cells even over long distances and promoting the transport of different cellular cargos. NTs are also involved in the intercellular spread of different pathogens and the deterioration of some neurological disorders. Transport processes via NTs may be controlled by cytoskeletal elements. NTs are frequently observed membrane projections in numerous mammalian cell lines, including various immune cells, but their functional significance in the ‘antibody factory’ B cells is poorly elucidated. Here, we report that as active channels, NTs of B-lymphoma cells can mediate bidirectional mitochondrial transport, promoted by the cooperation of two different cytoskeletal motor proteins, kinesin along microtubules and myosin VI along actin, and bidirectional transport processes are also supported by the heterogeneous arrangement of the main cytoskeletal filament systems of the NTs. We revealed that despite NTs and axons being different cell extensions, the mitochondrial transport they mediate may exhibit significant similarities. Furthermore, we found that microtubules may improve the stability and lifespan of B-lymphoma-cell NTs, while F-actin strengthens NTs by providing a structural framework for them. Our results may contribute to a better understanding of the regulation of the major cells of humoral immune response to infections. LA - English DB - MTMT ER - TY - JOUR AU - Rosano, Dalia AU - Sofyali, Emre AU - Dhiman, Heena AU - Ghirardi, Chiara AU - Ivanoiu, Diana AU - Heide, Timon AU - Vingiani, Andrea AU - Bertolotti, Alessia AU - Pruneri, Giancarlo AU - Canale, Eleonora AU - Dewhurst, Hannah F AU - Saha, Debjani AU - Slaven, Neil AU - Barozzi, Iros AU - Li, Tong AU - Zemlyanskiy, Grigory AU - Phillips, Henry AU - James, Chela AU - Győrffy, Balázs AU - Lynn, Claire AU - Cresswell, George D AU - Rehman, Farah AU - Noberini, Roberta AU - Bonaldi, Tiziana AU - Sottoriva, Andrea AU - Magnani, Luca TI - Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells JF - CANCER DISCOVERY J2 - CANCER DISCOV PY - 2024 SN - 2159-8274 DO - 10.1158/2159-8290.CD-23-1161 UR - https://m2.mtmt.hu/api/publication/34763944 ID - 34763944 N1 - * Megosztott szerzőség AB - Patients with estrogen receptor-positive breast cancer receive adjuvant endocrine therapies (ET) that delay relapse by targeting clinically undetectable micrometastatic deposits. Yet, up to 50% of patients relapse even decades after surgery through unknown mechanisms likely involving dormancy. To investigate genetic and transcriptional changes underlying tumor awakening, we analyzed late relapse patients and longitudinally profiled a rare cohort treated with long-term neoadjuvant ETs until progression. Next, we developed an in vitro evolutionary study to record the adaptive strategies of individual lineages in unperturbed parallel experiments. Our data demonstrate that ETs induce nongenetic cell state transitions into dormancy in a stochastic subset of cells via epigenetic reprogramming. Single lineages with divergent phenotypes awaken unpredictably in the absence of recurrent genetic alterations. Targeting the dormant epigenome shows promising activity against adapting cancer cells. Overall, this study uncovers the contribution of epigenetic adaptation to the evolution of resistance to ETs.This study advances the understanding of therapy-induced dormancy with potential clinical implications for breast cancer. Estrogen receptor-positive breast cancer cells adapt to endocrine treatment by entering a dormant state characterized by strong heterochromatinization with no recurrent genetic changes. Targeting the epigenetic rewiring impairs the adaptation of cancer cells to ETs. LA - English DB - MTMT ER - TY - BOOK AU - Bugyi, Beáta AU - Gaszler, Péter AU - Rauan, Sakenov AU - Szütsné Tóth, Mónika Ágnes AU - Leipold Vig, Andrea TI - BioX: Math in the Lab PB - PTE ÁOK Orvosi Biológiai Intézet CY - Pécs PY - 2024 SN - 9789636262419 UR - https://m2.mtmt.hu/api/publication/34742597 ID - 34742597 LA - English DB - MTMT ER - TY - JOUR AU - Radenkovic, Silvia AU - Budhraja, Rohit AU - Klein-Gunnewiek, Teun AU - King, Alexia Tyler AU - Bhatia, Tarun N AU - Ligezka, Anna N AU - Driesen, Karen AU - Shah, Rameen AU - Ghesquière, Bart AU - Pandey, Akhilesh AU - Kasri, Nael Nadif AU - Sloan, Steven A AU - Morava-Kozicz, Éva AU - Kozicz, Tamás TI - Neural and metabolic dysregulation in PMM2-deficient human in vitro neural models. JF - CELL REPORTS J2 - CELL REP VL - 43 PY - 2024 IS - 3 PG - 25 SN - 2211-1247 DO - 10.1016/j.celrep.2024.113883 UR - https://m2.mtmt.hu/api/publication/34729568 ID - 34729568 N1 - Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, United States Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States Department of Human Genetics, Radboud University Medical Centre, Nijmegen, XZ 6525, Netherlands Department of Human Genetics, Emory University, Atlanta, GA 30322, United States Metabolomics Expertise Center, VIB-KU Leuven, Leuven, 3000, Belgium Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, United States Laboratory of Applied Mass Spectrometry, KU Leuven, Leuven, 3000, Belgium Manipal Academy of Higher Education (MAHE), Karnataka, Manipal, 576104, India Department of Biophysics, University of Pécs Medical School, Pécs, 7624, Hungary Department of Anatomy, University of Pécs Medical School, Pécs, 7624, Hungary Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, United States Export Date: 18 March 2024 Correspondence Address: Kozicz, T.; Department of Clinical Genomics, United States; email: tamas.kozicz@mssm.edu AB - Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a rare inborn error of metabolism caused by deficiency of the PMM2 enzyme, which leads to impaired protein glycosylation. While the disorder presents with primarily neurological symptoms, there is limited knowledge about the specific brain-related changes caused by PMM2 deficiency. Here, we demonstrate aberrant neural activity in 2D neuronal networks from PMM2-CDG individuals. Utilizing multi-omics datasets from 3D human cortical organoids (hCOs) derived from PMM2-CDG individuals, we identify widespread decreases in protein glycosylation, highlighting impaired glycosylation as a key pathological feature of PMM2-CDG, as well as impaired mitochondrial structure and abnormal glucose metabolism in PMM2-deficient hCOs, indicating disturbances in energy metabolism. Correlation between PMM2 enzymatic activity in hCOs and symptom severity suggests that the level of PMM2 enzyme function directly influences neurological manifestations. These findings enhance our understanding of specific brain-related perturbations associated with PMM2-CDG, offering insights into the underlying mechanisms and potential directions for therapeutic interventions. LA - English DB - MTMT ER - TY - JOUR AU - Paniagua-Herranz, Lucía AU - Moreno, Irene AU - Nieto-Jiménez, Cristina AU - Garcia-Lorenzo, Esther AU - Díaz-Tejeiro, Cristina AU - Sanvicente, Adrián AU - Doger, Bernard AU - Pedregal, Manuel AU - Ramón, Jorge AU - Bartolomé, Jorge AU - Manzano, Arancha AU - Győrffy, Balázs AU - Gutierrez-Uzquiza, Álvaro AU - Pérez Segura, Pedro AU - Calvo, Emiliano AU - Moreno, Víctor AU - Ocana, Alberto TI - Genomic and Immunologic Correlates in Prostate Cancer with High Expression of KLK2 JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 25 PY - 2024 IS - 4 PG - 14 SN - 1661-6596 DO - 10.3390/ijms25042222 UR - https://m2.mtmt.hu/api/publication/34725864 ID - 34725864 N1 - * Megosztott szerzőség AB - The identification of surfaceome proteins is a main goal in cancer research to design antibody-based therapeutic strategies. T cell engagers based on KLK2, a kallikrein specifically expressed in prostate cancer (PRAD), are currently in early clinical development. Using genomic information from different sources, we evaluated the immune microenvironment and genomic profile of prostate tumors with high expression of KLK2. KLK2 was specifically expressed in PRAD but it was not significant associated with Gleason score. Additionally, KLK2 expression did not associate with the presence of any immune cell population and T cell activating markers. A mild correlation between the high expression of KLK2 and the deletion of TMPRSS2 was identified. KLK2 expression associated with high levels of surface proteins linked with a detrimental response to immune checkpoint inhibitors (ICIs) including CHRNA2, FAM174B, OR51E2, TSPAN1, PTPRN2, and the non-surface protein TRPM4. However, no association of these genes with an outcome in PRAD was observed. Finally, the expression of these genes in PRAD did not associate with an outcome in PRAD and any immune populations. We describe the immunologic microenvironment on PRAD tumors with a high expression of KLK2, including a gene signature linked with an inert immune microenvironment, that predicts the response to ICIs in other tumor types. Strategies targeting KLK2 with T cell engagers or antibody-drug conjugates will define whether T cell mobilization or antigen release and stimulation of immune cell death are sufficient effects to induce clinical activity. LA - English DB - MTMT ER - TY - JOUR AU - Nehr-Majoros, Andrea Kinga AU - Erostyák, János AU - Fenyvesi, Éva AU - Szabó-Meleg, Edina AU - Szőcs, Levente AU - Sétáló, György (ifj.) AU - Helyes, Zsuzsanna AU - Szőke, Éva TI - Cyclodextrin derivatives decrease Transient Receptor Potential vanilloid 1 and Ankyrin 1 ion channel activation via altering the surrounding membrane microenvironment by cholesterol depletion JF - FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY J2 - FRONT CELL DEV BIOL VL - 12 PY - 2024 PG - 13 SN - 2296-634X DO - 10.3389/fcell.2024.1334130 UR - https://m2.mtmt.hu/api/publication/34689825 ID - 34689825 AB - Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) are nonselective cation channels expressed in primary sensory neurons and several other non-neuronal structures such as immune cells, keratinocytes, and vascular smooth muscle cells. They play important roles in nociception, pain processing and their chanellopathies are associated with the development of several pathological conditions. They are located in cholesterol- and sphingolipid-rich membrane lipid raft regions serving as platforms to modulate their activations. We demonstrated earlier that disruption of these lipid rafts leads to decreased TRP channel activation and exerts analgesic effects. Cyclodextrins are macrocyclic molecules able to form host-guest complexes with cholesterol and deplete it from the membrane lipid rafts. The aim of this study was to investigate 8 structurally different (methylated and non-methylated) CD derivatives on cell viability, mitochondrial membrane potential, membrane composition and activation abilities of the TRPV1 and TRPA1 channels. We showed that non-methylated derivatives have preferable safety profiles compared to methylated ones. Furthermore, methylated derivatives reduced mitochondrial membrane potential. However, all investigated derivatives influence the ordered cell membrane structure depleting membrane cholesterol and inhibit the TRPV1 agonist capsaicin- and the TRPA1 agonist allyl isothiocyanate-induced Ca 2+− influx. This mechanism of action might provide novel perspectives for the development of peripherally acting analgesics via indirectly decreasing the generation and transmission of nociceptive signals. LA - English DB - MTMT ER - TY - JOUR AU - He, YongLe AU - Collado, Jinnette Tolentino AU - Iuliano, James N. AU - Woroniecka, Helena A. AU - Hall, Christopher R. AU - Gil, Agnieszka A. AU - Laptenok, Sergey P. AU - Greetham, Gregory M. AU - Illarionov, Boris AU - Bacher, Adelbert AU - Fischer, Markus AU - French, Jarrod B. AU - Lukács, András Szilárd AU - Meech, Stephen R. AU - Tonge, Peter J. TI - Elucidating the Signal Transduction Mechanism of the Blue-Light-Regulated Photoreceptor YtvA: From Photoactivation to Downstream Regulation JF - ACS CHEMICAL BIOLOGY J2 - ACS CHEM BIOL VL - 19 PY - 2024 IS - 3 SP - 696 EP - 706 PG - 11 SN - 1554-8929 DO - 10.1021/acschembio.3c00722 UR - https://m2.mtmt.hu/api/publication/34672739 ID - 34672739 AB - The blue-light photoreceptor YtvA from Bacillus subtilis has an N-terminal flavin mononucleotide (FMN)-binding light-oxygen-voltage (LOV) domain that is fused to a C-terminal sulfate transporter and anti-σ factor antagonist (STAS) output domain. To interrogate the signal transduction pathway that leads to photoactivation, the STAS domain was replaced with a histidine kinase, so that photoexcitation of the flavin could be directly correlated with biological activity. N94, a conserved Asn that is hydrogen bonded to the FMN C2═O group, was replaced with Ala, Asp, and Ser residues to explore the role of this residue in triggering the structural dynamics that activate the output domain. Femtosecond to millisecond time-resolved multiple probe spectroscopy coupled with a fluorescence polarization assay revealed that the loss of the hydrogen bond between N94 and the C2═O group decoupled changes in the protein structure from photoexcitation. In addition, alterations in N94 also decreased the stability of the Cys-FMN adduct formed in the light-activated state by up to a factor of ∼25. Collectively, these studies shed light on the role of the hydrogen bonding network in the LOV β-scaffold in signal transduction. LA - English DB - MTMT ER - TY - JOUR AU - Ujfalusi-Pozsonyi, Kinga AU - Bódis, Emőke AU - Nyitrai, Miklós AU - Kengyel, András Miklós AU - Telek, Elek AU - Pécsi, Ildikó AU - Fekete, Zsuzsanna AU - Varnyuné Kis-Bicskei, Nikolett AU - Mas, C. AU - Moussaoui, D. AU - Pernot, P. AU - Tully, M. D. AU - Weik, M. AU - Schirò, G. AU - Kapetanaki, Sofia AU - Lukács, András Szilárd TI - ATP-dependent conformational dynamics in a photoactivated adenylate cyclase revealed by fluorescence spectroscopy and small-angle X-ray scattering JF - COMMUNICATIONS BIOLOGY J2 - COMMUN BIOL VL - 7 PY - 2024 IS - 1 PG - 15 SN - 2399-3642 DO - 10.1038/s42003-024-05842-1 UR - https://m2.mtmt.hu/api/publication/34555708 ID - 34555708 N1 - Department of Biophysics, Medical School, University of Pécs, Pécs, 7624, Hungary Univ. Grenoble Alpes, CNRS, CEA, EMBL, ISBG, Grenoble, F-38000, France European Synchrotron Radiation Facility (ESRF), Grenoble, France Institut de Biologie Structurale (IBS), Université Grenoble Alpes, CEA, CNRS, Grenoble, France Export Date: 19 February 2024 Correspondence Address: Lukács, A.; Department of Biophysics, Hungary; email: andras.lukacs@aok.pte.hu Correspondence Address: Kapetanaki, S.M.; Institut de Biologie Structurale (IBS), France; email: sofia.kapetanaki@aok.pte.hu AB - Structural insights into the photoactivated adenylate cyclases can be used to develop new ways of controlling cellular cyclic adenosine monophosphate (cAMP) levels for optogenetic and other applications. In this work, we use an integrative approach that combines biophysical and structural biology methods to provide insight on the interaction of adenosine triphosphate (ATP) with the dark-adapted state of the photoactivated adenylate cyclase from the cyanobacterium Oscillatoria acuminata (OaPAC). A moderate affinity of the nucleotide for the enzyme was calculated and the thermodynamic parameters of the interaction have been obtained. Stopped-flow fluorescence spectroscopy and small-angle solution scattering have revealed significant conformational changes in the enzyme, presumably in the adenylate cyclase (AC) domain during the allosteric mechanism of ATP binding to OaPAC with small and large-scale movements observed to the best of our knowledge for the first time in the enzyme in solution upon ATP binding. These results are in line with previously reported drastic conformational changes taking place in several class III AC domains upon nucleotide binding. LA - English DB - MTMT ER - TY - JOUR AU - Farkas, Dávid AU - Szikora, Szilárd AU - Jijumon, A S AU - Polgár, Tamás Ferenc AU - Patai, Roland AU - Szütsné Tóth, Mónika Ágnes AU - Bugyi, Beáta AU - Gajdos, Tamás AU - Bíró, Péter AU - Novák, Tibor AU - Erdélyi, Miklós AU - Mihály, József TI - Peripheral thickening of the sarcomeres and pointed end elongation of the thin filaments are both promoted by SALS and its formin interaction partners JF - PLOS GENETICS J2 - PLOS GENET VL - 20 PY - 2024 IS - 1 PG - 31 SN - 1553-7390 DO - 10.1371/journal.pgen.1011117 UR - https://m2.mtmt.hu/api/publication/34506131 ID - 34506131 N1 - Institute of Genetics, Biological Research Centre, Szeged, Hungary Institute of Biophysics, Biological Research Centre, Szeged, Hungary Doctoral School of Theoretical Medicine, University of Szeged, Szeged, Hungary University of Pécs, Medical School, Department of Biophysics, Pécs, Hungary Department of Optics and Quantum Electronics, University of Szeged, Szeged, Hungary University of Szeged, Department of Genetics, Szeged, Hungary Export Date: 29 January 2024 Correspondence Address: Mihály, J.; Institute of Genetics, Hungary; email: mihaly.jozsef@brc.hu AB - During striated muscle development the first periodically repeated units appear in the premyofibrils, consisting of immature sarcomeres that must undergo a substantial growth both in length and width, to reach their final size. Here we report that, beyond its well established role in sarcomere elongation, the Sarcomere length short (SALS) protein is involved in Z-disc formation and peripheral growth of the sarcomeres. Our protein localization data and loss-of-function studies in the Drosophila indirect flight muscle strongly suggest that radial growth of the sarcomeres is initiated at the Z-disc. As to thin filament elongation, we used a powerful nanoscopy approach to reveal that SALS is subject to a major conformational change during sarcomere development, which might be critical to stop pointed end elongation in the adult muscles. In addition, we demonstrate that the roles of SALS in sarcomere elongation and radial growth are both dependent on formin type of actin assembly factors. Unexpectedly, when SALS is present in excess amounts, it promotes the formation of actin aggregates highly resembling the ones described in nemaline myopathy patients. Collectively, these findings helped to shed light on the complex mechanisms of SALS during the coordinated elongation and thickening of the sarcomeres, and resulted in the discovery of a potential nemaline myopathy model, suitable for the identification of genetic and small molecule inhibitors. LA - English DB - MTMT ER -