TY - JOUR AU - Padányi, Rita AU - Farkas, Bianka Vivien AU - Tordai, Hedvig AU - Kiss, Bálint AU - Grubmüller, Helmut AU - Soya, Naoto AU - Lukács, Gergely L. AU - Kellermayer, Miklós AU - Hegedűs, Tamás TI - Nanomechanics combined with HDX reveals allosteric drug binding sites of CFTR NBD1 JF - COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL J2 - CSBJ VL - 20 PY - 2022 SP - 2587 EP - 2599 PG - 13 SN - 2001-0370 DO - 10.1016/j.csbj.2022.05.036 UR - https://m2.mtmt.hu/api/publication/32853643 ID - 32853643 AB - Cystic fibrosis (CF) is a frequent genetic disease in Caucasians that is caused by the deletion of F508 (DF508) in the nucleotide binding domain 1 (NBD1) of the CF transmembrane conductance regulator (CFTR). The DF508 compromises the folding energetics of the NBD1, as well as the folding of three other CFTR domains. Combination of FDA approved corrector molecules can efficiently but incompletely rescue the DF508-CFTR folding and stability defect. Thus, new pharmacophores that would reinstate the wildtype-like conformational stability of the DF508-NBD1 would be highly beneficial. The most prominent molecule, 5-bromoindole-3-acetic acid (BIA) that can thermally stabilize the NBD1 has low potency and efficacy. To gain insights into the NBD1 (un)folding dynamics and BIA binding site localization, we combined molecular dynamics (MD) simulations, atomic force spectroscopy (AFM) and hydrogendeuterium exchange (HDX) experiments. We found that the NBD1 a-subdomain with three adjacent strands from the b-subdomain plays an important role in early folding steps, when crucial non-native interactions are formed via residue F508. Our AFM and HDX experiments showed that BIA associates with this a-core region and increases the resistance of the DF508-NBD1 against mechanical unfolding, a phenomenon that could be exploited in future developments of folding correctors. (c) 2022 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). LA - English DB - MTMT ER - TY - JOUR AU - Naffa, Randa AU - Padányi, Rita AU - Ignácz, Attila AU - Hegyi, Zoltán AU - Jezsó, Bálint AU - Tóth, Sarolta AU - Varga, Karolina AU - Homolya, László AU - Hegedűs, Luca AU - Schlett, Katalin AU - Enyedi, Ágnes TI - The Plasma Membrane Ca2+ Pump PMCA4b Regulates Melanoma Cell Migration through Remodeling of the Actin Cytoskeleton JF - CANCERS J2 - CANCERS VL - 13 PY - 2021 IS - 6 PG - 25 SN - 2072-6694 DO - 10.3390/cancers13061354 UR - https://m2.mtmt.hu/api/publication/31925833 ID - 31925833 N1 - Funding Agency and Grant Number: Hungarian Scientific Research Development and Innovation Office [NKFIH K119223, K135811, K128123]; Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary; Stipendium Hungaricum Fellowships; [VEKOP-2.3.3-15-2016-00007] Funding text: Hungarian Scientific Research Development and Innovation Office (grant numbers: NKFIH K119223 and K135811 to A.E., K128123 to L.H. (Laszlo Homolya)), the Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary, within the framework of the Molecular Biology thematic program of the Semmelweis University (FIKP to A.E.), Stipendium Hungaricum Fellowships (awarded to R.N.), and VEKOP-2.3.3-15-2016-00007 (to K.S.). Department of Transfusiology, Semmelweis University, Budapest, H‐1089, Hungary Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, H‐1094, Hungary Department of Physiology and Neurobiology, Eötvös Loránd University, Budapest, H‐1117, Hungary Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt.2, Budapest, H‐1117, Hungary Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest, H‐1117, Hungary Versys Clinics, Budapest, H‐1138, Hungary Department of Thoracic Surgery, Ruhrlandklinik, University Clinic Essen, Essen, 45239, Germany Export Date: 24 July 2021 Correspondence Address: Enyedi, A.; Department of Transfusiology, Hungary; email: enyedi.agnes@med.semmelweis‐univ.hu LA - English DB - MTMT ER - TY - JOUR AU - Gáspárné Csizmadia, Georgina AU - Erdős, Gábor AU - Tordai, Hedvig AU - Padányi, Rita AU - Tosatto, Silvio AU - Dosztányi, Zsuzsanna AU - Hegedűs, Tamás TI - The MemMoRF database for recognizing disordered protein regions interacting with cellular membranes JF - NUCLEIC ACIDS RESEARCH J2 - NUCLEIC ACIDS RES VL - 49 PY - 2020 IS - D1 SP - D355 EP - D360 SN - 0305-1048 DO - 10.1093/nar/gkaa954 UR - https://m2.mtmt.hu/api/publication/31641470 ID - 31641470 N1 - Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, 1094, Hungary MTA-ELTE Lendület Bioinformatics Research Group, Department of Biochemistry, Eötvös Loránd University, Budapest, 1117, Hungary Department of Biomedical Sciences, University of Padua, Padua, 35131, Italy Cited By :3 Export Date: 31 March 2022 CODEN: NARHA Correspondence Address: Hegedűs, T.; Department of Biophysics and Radiation Biology, Hungary; email: hegedus@hegelab.org LA - English DB - MTMT ER - TY - JOUR AU - Hegedűs, L. AU - Zámbó, Boglárka AU - Pászty, Katalin AU - Padányi, Rita AU - Varga, Karolina AU - Penniston, J.T. AU - Enyedi, Ágnes TI - Molecular Diversity of Plasma Membrane Ca2+ Transporting ATPases: Their Function Under Normal and Pathological Conditions JF - ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY J2 - ADV EXP MED BIOL VL - 1131 PY - 2020 SP - 93 EP - 129 PG - 37 SN - 0065-2598 DO - 10.1007/978-3-030-12457-1_5 UR - https://m2.mtmt.hu/api/publication/30924863 ID - 30924863 AB - Plasma membrane Ca2+ transport ATPases (PMCA1-4, ATP2B1-4) are responsible for removing excess Ca2+ from the cell in order to keep the cytosolic Ca2+ ion concentration at the low level essential for normal cell function. While these pumps take care of cellular Ca2+ homeostasis they also change the duration and amplitude of the Ca2+ signal and can create Ca2+ gradients across the cell. This is accomplished by generating more than twenty PMCA variants each having the character – fast or slow response, long or short memory, distinct interaction partners and localization signals – that meets the specific needs of the particular cell-type in which they are expressed. It has become apparent that these pumps are essential to normal tissue development and their malfunctioning can be linked to different pathological conditions such as certain types of neurodegenerative and heart diseases, hearing loss and cancer. In this chapter we summarize the complexity of PMCA regulation and function under normal and pathological conditions with particular attention to recent developments of the field. © Springer Nature Switzerland AG 2020. LA - English DB - MTMT ER - TY - JOUR AU - Farkas, Bianka Vivien AU - Tordai, Hedvig AU - Padányi, Rita AU - Tordai, Attila AU - Gera, János AU - Paragi, Gábor AU - Hegedűs, Tamás TI - Discovering the chloride pathway in the CFTR channel JF - CELLULAR AND MOLECULAR LIFE SCIENCES J2 - CELL MOL LIFE SCI VL - 77 PY - 2020 IS - 4 SP - 765 EP - 778 PG - 12 SN - 1420-682X DO - 10.1007/s00018-019-03211-4 UR - https://m2.mtmt.hu/api/publication/30745347 ID - 30745347 N1 - Funding Agency and Grant Number: Semmelweis Egyetem [Sci_Innov18] Funding Source: Medline; Cystic Fibrosis Foundation (US) [HEGEDU18I0] Funding Source: Medline; Nemzeti Kutatasi, Fejlesztesi es Innovacios Hivatal (HU) [K127961, K111678] Funding Source: Medline Cited By :2 Export Date: 31 August 2021 CODEN: CMLSF Correspondence Address: Hegedűs, T.; Department of Biophysics and Radiation Biology, Hungary; email: hegedus@hegelab.org LA - English DB - MTMT ER - TY - JOUR AU - Varga, Karolina AU - Hollósi, Anna AU - Pászty, Katalin AU - Hegedus, L. AU - Szakács, Gergely AU - Tímár, József AU - Papp, B. AU - Enyedi, Ágnes AU - Padányi, Rita TI - Expression of calcium pumps is differentially regulated by histone deacetylase inhibitors and estrogen receptor alpha in breast cancer cells JF - BMC CANCER J2 - BMC CANCER VL - 18 ET - 0 PY - 2018 IS - 1 PG - 17 SN - 1471-2407 DO - 10.1186/s12885-018-4945-x UR - https://m2.mtmt.hu/api/publication/30317833 ID - 30317833 N1 - 2nd Department of Pathology, Semmelweis University, Budapest, Hungary Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary Department of Thoracic Surgery, Ruhrlandklinik, University Clinic Essen, University Duisburg-Essen, Duisburg, Germany Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary Institute of Cancer Research, Medical University Vienna, Vienna, Austria U978, Institut National de la Santé et de la Recherche Médicale, Université Paris-13, PRES Sorbonne Paris-Cité, Bobigny, France Cited By :25 Export Date: 10 March 2023 CODEN: BCMAC Correspondence Address: Padányi, R.; 2nd Department of Pathology, Hungary; email: padanyi.rita@med.semmelweis-univ.hu AB - Background: Remodeling of Ca2+ signaling is an important step in cancer progression, and altered expression of members of the Ca2+ signaling toolkit including the plasma membrane Ca2+ ATPases (PMCA proteins encoded by ATP2B genes) is common in tumors. Methods: In this study PMCAs were examined in breast cancer datasets and in a variety of breast cancer cell lines representing different subtypes. We investigated how estrogen receptor alpha (ER-α) and histone deacetylase (HDAC) inhibitors regulate the expression of these pumps. Results: Three distinct datasets displayed significantly lower ATP2B4 mRNA expression in invasive breast cancer tissue samples compared to normal breast tissue, whereas the expression of ATP2B1 and ATP2B2 was not altered. Studying the protein expression profiles of Ca2+ pumps in a variety of breast cancer cell lines revealed low PMCA4b expression in the ER-α positive cells, and its marked upregulation upon HDAC inhibitor treatments. PMCA4b expression was also positively regulated by the ER-α pathway in MCF-7 cells that led to enhanced Ca2+ extrusion capacity in response to 17β-estradiol (E2) treatment. E2-induced PMCA4b expression was further augmented by HDAC inhibitors. Surprisingly, E2 did not affect the expression of PMCA4b in other ER-α positive cells ZR-75-1, T-47D and BT-474. These findings were in good accordance with ChIP-seq data analysis that revealed an ER-α binding site in the ATP2B4 gene in MCF-7 cells but not in other ER-α positive tumor cells. In the triple negative cells PMCA4b expression was relatively high, and the effect of HDAC inhibitor treatment was less pronounced as compared to that of the ER-α positive cells. Although, the expression of PMCA4b was relatively high in the triple negative cells, a fraction of the protein was found in intracellular compartments that could interfere with the cellular function of the protein. Conclusions: Our results suggest that the expression of Ca2+ pumps is highly regulated in breast cancer cells in a subtype specific manner. Our results suggest that hormonal imbalances, epigenetic modifications and impaired protein trafficking could interfere with the expression and cellular function of PMCA4b in the course of breast cancer progression. © 2018 The Author(s). LA - English DB - MTMT ER - TY - JOUR AU - Hegedűs, Luca AU - Padányi, Rita AU - Molnár, Judit AU - Pászty, Katalin AU - Varga, Karolina AU - Kenessey, István AU - Sárközy, Eszter AU - Wolf, Matthias AU - Grusch, Michael AU - Hegyi, Zoltán AU - Homolya, László AU - Aigner, Clemens AU - Garay, Tamás AU - Hegedűs, Balázs AU - Tímár, József AU - Kállay, Enikö AU - Enyedi, Ágnes TI - Histone deacetylase inhibitor treatment increases the expression of the plasma membrane Ca2+ pump PMCA4b and inhibits migration of melanoma cells independent of ERK JF - FRONTIERS IN ONCOLOGY J2 - FRONT ONCOL VL - 7 PY - 2017 IS - May PG - 13 SN - 2234-943X DO - 10.3389/fonc.2017.00095 UR - https://m2.mtmt.hu/api/publication/3215325 ID - 3215325 N1 - Department of Thoracic Surgery, Ruhrlandklinik, University Clinic Essen, Essen, Germany Department of Pathophysiology and Allergy Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria II Institute of Pathology, Semmelweis University, Budapest, Hungary Molecular Biophysics Research Group of the Hungarian Academy of Sciences, Department of Biophysics, Semmelweis University, Budapest, Hungary MTA-SE-NAP Brain Metastasis Research Group of the Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary Molecular Oncology Research Group of the Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary Cited By :16 Export Date: 10 March 2023 Correspondence Address: Enyedi, A.; II Institute of Pathology, Hungary; email: enyedi.agnes@med.semmelweis-univ.hu LA - English DB - MTMT ER - TY - JOUR AU - Zámbó, Boglárka AU - Várady, György AU - Padányi, Rita AU - Szabó, Edit Zsuzsanna AU - Németh, Adrienn AU - Langó, Tamás AU - Enyedi, Ágnes AU - Sarkadi, Balázs TI - Decreased calcium pump expression in human erythrocytes is connected to a minor haplotype in the ATP2B4 gene JF - CELL CALCIUM J2 - CELL CALCIUM VL - 65 PY - 2017 SP - 73 EP - 79 PG - 7 SN - 0143-4160 DO - 10.1016/j.ceca.2017.02.001 UR - https://m2.mtmt.hu/api/publication/3190054 ID - 3190054 N1 - Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary 2nd Department of Pathology, Faculty of Medicine, Semmelweis University, Ulloi ut 26., Budapest, 1085, Hungary Molecular Oncology Research Group of the Hungarian Academy of Sciences and Semmelweis University, Ulloi ut 26., Budapest, 1085, Hungary MTA-SE Molecular Biophysics Research Group, Department of Biophysics and Radiation Biology, Semmelweis University, Tuzolto u. 37-43., Budapest, 1094, Hungary Cited By :22 Export Date: 10 February 2024 CODEN: CECAD Correspondence Address: Sarkadi, B.; Institute of Enzymology, Magyar Tudosok krt. 2, Hungary; email: sarkadi@biomembrane.hu Chemicals/CAS: adenosine triphosphatase (calcium); hemoglobin, 9008-02-0; ATP2B4 protein, human; Hemoglobins; Plasma Membrane Calcium-Transporting ATPases AB - Plasma membrane Ca2+-ATPases are key calcium exporter proteins in most tissues, and PMCA4b is the main calcium transporter in the human red blood cells (RBCs). In order to assess the expression level of PMCA4b, we have developed a flow cytometry and specific antibody binding method to quantitatively detect this protein in the erythrocyte membrane. Interestingly, we found several healthy volunteers showing significantly reduced expression of RBC-PMCA4b. Western blot analysis of isolated RBC membranes confirmed this observation, and indicated that there are no compensatory alterations in other PMCA isoforms. In addition, reduced PMCA4b levels correlated with a lower calcium extrusion capacity in these erythrocytes. When exploring the potential genetic background of the reduced PMCA4b levels, we found no missense mutations in the ATP2B4 coding regions, while a formerly unrecognized minor haplotype in the predicted second promoter region closely correlated with lower erythrocyte PMCA4b protein levels. In recent GWA studies, SNPs in this ATP2B4 haplotype have been linked to reduced mean corpuscular hemoglobin concentrations (MCHC), and to protection against malaria infection. Our data suggest that an altered regulation of gene expression is responsible for the reduced RBC-PMCA4b levels that is probably linked to the development of human disease-related phenotypes. LA - English DB - MTMT ER - TY - JOUR AU - Hegedűs, Luca AU - Garay, Tamás AU - Molnár, Eszter AU - Varga, Karolina AU - Bilecz, Ágnes AU - Török, Szilvia AU - Padányi, Rita AU - Pászty, Katalin AU - Wolf, M AU - Grusch, M AU - Kállay, E AU - Döme, Balázs AU - Berger, W AU - Hegedűs, Balázs AU - Enyedi, Ágnes TI - The plasma membrane Ca2+ pump PMCA4b inhibits the migratory and metastatic activity of BRAF mutant melanoma cells JF - INTERNATIONAL JOURNAL OF CANCER J2 - INT J CANCER VL - 140 PY - 2017 IS - 12 SP - 2758 EP - 2770 PG - 13 SN - 0020-7136 DO - 10.1002/ijc.30503 UR - https://m2.mtmt.hu/api/publication/3145338 ID - 3145338 N1 - Department of Pathophysiology and Allergy Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria 2nd Department of Pathology, Semmelweis University, Budapest, Hungary Department of Biological Physics, Eötvös University, Budapest, Hungary National Koranyi Institute of Pulmonology, Budapest, Hungary Molecular Biophysics Research Group of the Hungarian Academy of Sciences and Department of Biophysics, Semmelweis University, Budapest, Hungary Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria Department of Surgery, Division of Thoracic Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria Department of Thoracic Surgery, Ruhrlandklinik, University Clinic Essen, Essen, Germany Molecular Oncology Research Group of the Hungarian Academy of Sciences and 2nd Department of Pathology, Semmelweis University, Budapest, Hungary Cited By :19 Export Date: 15 September 2021 CODEN: IJCNA Correspondence Address: Hegedũs, B.; Department of Surgery, Austria; email: balazs.hegedues@rlk.uk-essen.de AB - Oncogenic mutations of BRAF lead to constitutive ERK activity that supports melanoma cell growth and survival. While Ca2+ signaling is a well-known regulator of tumor progression, the crosstalk between Ca2+ signaling and the Ras-BRAF-MEK-ERK pathway is much less explored. Here we show that in BRAF mutant melanoma cells the abundance of the plasma membrane Ca2+ ATPase isoform 4b (PMCA4b, ATP2B4) is low at baseline but markedly elevated by treatment with the mutant BRAF specific inhibitor vemurafenib. In line with these findings gene expression microarray data also shows decreased PMCA4b expression in cutaneous melanoma when compared to benign nevi. The MEK inhibitor selumetinib-similarly to that of the BRAF-specific inhibitor-also increases PMCA4b levels in both BRAF and NRAS mutant melanoma cells suggesting that the MAPK pathway is involved in the regulation of PMCA4b expression. The increased abundance of PMCA4b in the plasma membrane enhances [Ca2+ ]i clearance from cells after Ca2+ entry. Moreover we show that both vemurafenib treatment and PMCA4b overexpression induce marked inhibition of migration of BRAF mutant melanoma cells. Importantly, reduced migration of PMCA4b expressing BRAF mutant cells is associated with a marked decrease in their metastatic potential in vivo. Taken together, our data reveal an important crosstalk between Ca2+ signaling and the MAPK pathway through the regulation of PMCA4b expression and suggest that PMCA4b is a previously unrecognized metastasis suppressor. LA - English DB - MTMT ER - TY - JOUR AU - Padányi, Rita AU - Pászty, Katalin AU - Hegedűs, Luca AU - Varga, Karolina AU - Béla, Papp AU - John, T Penniston AU - Enyedi, Ágnes TI - Multifaceted plasma membrane Ca2+ pumps: From structure to intracellular Ca2+ handling and cancer JF - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH J2 - BBA-MOL CELL RES VL - 1863 PY - 2016 IS - 6 SP - 1351 EP - 1363 PG - 13 SN - 0167-4889 DO - 10.1016/j.bbamcr.2015.12.011 UR - https://m2.mtmt.hu/api/publication/3015469 ID - 3015469 N1 - The first two authors contributed equally to this work. (Megosztott elsőszerzők) LA - English DB - MTMT ER -