@article{MTMT:36173682, title = {pLMMoRF: A web server that accurately predicts membrane-interacting molecular recognition features by employing a protein language model.}, url = {https://m2.mtmt.hu/api/publication/36173682}, author = {Csepi, Máté and Berta, Blanka and Basu, Sushmita and Kurgan, Lukasz and Hegedűs, Tamás}, doi = {10.1016/j.jmb.2025.169236}, journal-iso = {J MOL BIOL}, journal = {JOURNAL OF MOLECULAR BIOLOGY}, unique-id = {36173682}, issn = {0022-2836}, abstract = {Interactions between proteins and lipids are crucial for numerous cellular processes. Some of the lipid interacting segments in protein sequences are intrinsically disordered regions (IDRs), which may gain secondary structures upon binding. We collected experimentally annotated lipid-interacting IDRs, named membrane molecular recognition features (MemMoRFs). We used this dataset to develop and test an accurate and relatively fast sequence-based MemMoRF predictor, pLMMoRF, thereby supporting tedious and costly experimental identification of MemMoRFs. Our predictor utilizes a protein language model (pLM) which we processed to generate inputs to a deep convolutional neural network. We considered various pLMs (ESM-2, ProstT5, ProtT5 and Ankh) and applied feature selection to reduce their outputs, creating a more compact neural network model. pLMMoRF leverages the Ankh-based model, selected for its higher accuracy compared to our other models. Tests on low similarity test datasets demonstrate that pLMMoRF is more accurate than the sole current predictor of MemMoRFs, CoMemMoRFPred. Moreover, pLMMoRF has a relatively small computational footprint because of the compact network size and use of dedicated GPU nodes. This allowed us to make MemMoRF predictions for the human proteome. We analyzed these predictions and made them publicly available, facilitating an improved understanding of functions of membrane-coupled proteins. Our work underscores the importance of selecting key embedding features to enhance predictive performance and reduce computational footprint of sequence-based predictors of protein functions. The web server for the pLMMoRF predictor and the predictions for human proteins are freely available at https://plmmorf.hegelab.org.}, keywords = {machine learning; Intrinsically disordered protein regions; Protein language model; membrane interacting molecular recognition feature}, year = {2025}, eissn = {1089-8638}, orcid-numbers = {Hegedűs, Tamás/0000-0002-0331-9629} } @article{MTMT:36149599, title = {Revisiting the Role of the Leucine Plug/Valve in the Human ABCG2 Multidrug Transporter}, url = {https://m2.mtmt.hu/api/publication/36149599}, author = {Mózner, Orsolya and Szabó, Kata Sára and Bodnár, Anikó and Koppány, Csenge and Homolya, László and Várady, György and Hegedűs, Tamás and Sarkadi, Balázs and Telbisz, Ágnes Mária}, doi = {10.3390/ijms26094010}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {26}, unique-id = {36149599}, issn = {1661-6596}, abstract = {In the human ABCG2 (ATP Binding Casette transporter G2/BCRP/MXR) multidrug transporter, a so-called “leucin plug/valve” (a.a. L554/L555) has been suggested to facilitate substrate exit and the coupling of drug transport to ATPase activity. In this work, we analyzed the effects of selected variants in this region by expressing these variants, both in mammalian and Sf9 insect cells. We found that, in mammalian cells, the L554A, L554F, L555F, and a combination of L554F/L555F variants of ABCG2 were functional, were processed to the plasma membrane, and exhibited substrate transport activity similar to the wild-type ABCG2, while the L555A and L554A/L555A mutants were poorly expressed and processed in mammalian cells. In Sf9 cells, all the variants were expressed at similar levels; still, the L555A and L554A/L555A variants lost all transport-related functions, while the L554F and L555F variants had reduced dye transport and altered substrate-stimulated ATPase activity. In molecular dynamics simulations, the mutant variants exhibited highly rearranged contacts in the central transmembrane helices; thus, alterations in folding, trafficking, and function can be expected to occur. Our current studies reinforce the importance of L554/L555 in ABCG2 folding and function, while they do not support the specific role of this region in selective substrate handling and show a general reduction in the coupling of drug transport to ATPase activity in the mutant versions.}, year = {2025}, eissn = {1422-0067}, orcid-numbers = {Mózner, Orsolya/0000-0001-5784-7702; Szabó, Kata Sára/0000-0002-5388-5127; Bodnár, Anikó/0009-0006-0849-7367; Homolya, László/0000-0003-1639-8140; Várady, György/0000-0003-2012-9680; Hegedűs, Tamás/0000-0002-0331-9629; Sarkadi, Balázs/0000-0003-0592-4539; Telbisz, Ágnes Mária/0000-0003-0972-4606} } @article{MTMT:36132706, title = {A key residue of the extracellular gate provides quality control contributing to ABCG substrate specificity}, url = {https://m2.mtmt.hu/api/publication/36132706}, author = {Xia, J. and Siffert, A. and Torres Constante, Karen Odalys and Iacobini, F. and Banasiak, J. and Pakuła, K. and Ziegler, J. and Rosahl, S. and Ferro, N. and Jasiński, M. and Hegedűs, Tamás and Geisler, M.M.}, doi = {10.1038/s41467-025-59518-3}, journal-iso = {NAT COMMUN}, journal = {NATURE COMMUNICATIONS}, volume = {16}, unique-id = {36132706}, issn = {2041-1723}, abstract = {For G-type ATP-binding cassette (ABC) transporters, a hydrophobic “di-leucine motif” as part of a hydrophobic extracellular gate has been described to separate a large substrate-binding cavity from a smaller upper cavity and proposed to act as a valve controlling drug extrusion. Here, we show that an L704F mutation in the hydrophobic extracellular gate of Arabidopsis ABCG36/PDR8/PEN3 uncouples the export of the auxin precursor indole-3-butyric acid (IBA) from that of the defense compound camalexin (CLX). Molecular dynamics simulations reveal increased free energy for CLX translocation in ABCG36L704F and reduced CLX contacts within the binding pocket proximal to the extracellular gate region. Mutation L704Y enables export of structurally related non-ABCG36 substrates, IAA, and indole, indicating allosteric communication between the extracellular gate and distant transport pathway regions. An evolutionary analysis identifies L704 as a Brassicaceae family-specific key residue of the extracellular gate that controls the identity of chemically similar substrates. In summary, our work supports the conclusion that L704 is a key residue of the extracellular gate that provides a final quality control contributing to ABCG substrate specificity, allowing for balance of growth-defense trade-offs. © The Author(s) 2025.}, year = {2025}, eissn = {2041-1723}, orcid-numbers = {Torres Constante, Karen Odalys/0000-0002-7263-6425; Hegedűs, Tamás/0000-0002-0331-9629} } @article{MTMT:35306993, title = {SARS-CoV-2 envelope protein alters calcium signaling via SERCA interactions}, url = {https://m2.mtmt.hu/api/publication/35306993}, author = {Berta, Blanka and Tordai, Hedvig and Lukács, G.L. and Papp, B. and Enyedi, Ágnes and Padányi, Rita and Hegedűs, Tamás}, doi = {10.1038/s41598-024-71144-5}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {14}, unique-id = {35306993}, year = {2024}, eissn = {2045-2322}, orcid-numbers = {Tordai, Hedvig/0000-0002-0875-5569; Enyedi, Ágnes/0000-0002-7366-9376; Padányi, Rita/0000-0001-7798-0463; Hegedűs, Tamás/0000-0002-0331-9629} } @article{MTMT:34724664, title = {PtdIns4p is required for the autophagosomal recruitment of STX17 (syntaxin 17) to promote lysosomal fusion}, url = {https://m2.mtmt.hu/api/publication/34724664}, author = {Laczkó-Dobos, Hajnalka and Bhattacharjee, Arindam and Maddali, Asha Kiran and Kincses, András and Abuammar, Hussein and Sebőkné Nagy, Krisztina and Páli, Tibor and Dér, András and Hegedűs, Tamás and Csordás, Gábor and Juhász, Gábor}, doi = {10.1080/15548627.2024.2322493}, journal-iso = {AUTOPHAGY}, journal = {AUTOPHAGY}, volume = {20}, unique-id = {34724664}, issn = {1554-8627}, abstract = {ABSTRACT The autophagosomal SNARE STX17 (syntaxin 17) promotes lysosomal fusion and degradation, but its autophagosomal recruitment is incompletely understood. Notably, PtdIns4P is generated on autophagosomes and promotes fusion through an unknown mechanism. Here we show that soluble recombinant STX17 is spontaneously recruited to negatively charged liposomes and adding PtdIns4P to liposomes containing neutral lipids is sufficient for its recruitment. Consistently, STX17 colocalizes with PtdIns4P-positive autophagosomes in cells, and specific inhibition of PtdIns4P synthesis on autophagosomes prevents its loading. Molecular dynamics simulations indicate that C-terminal positively charged amino acids establish contact with membrane bilayers containing negatively charged PtdIns4P. Accordingly, Ala substitution of Lys and Arg residues in the C terminus of STX17 abolishes membrane binding and impairs its autophagosomal recruitment. Finally, only wild type but not Ala substituted STX17 expression rescues the autophagosome-lysosome fusion defect of STX17 loss-of-function cells. We thus identify a key step of autophagosome maturation that promotes lysosomal fusion.}, year = {2024}, eissn = {1554-8635}, pages = {1639-1650}, orcid-numbers = {Páli, Tibor/0000-0003-1649-1097; Hegedűs, Tamás/0000-0002-0331-9629; Csordás, Gábor/0000-0001-6871-6839; Juhász, Gábor/0000-0001-8548-8874} } @article{MTMT:33731782, title = {Plasma membrane Ca2+ pump isoform 4 function in cell migration and cancer metastasis}, url = {https://m2.mtmt.hu/api/publication/33731782}, author = {Naffa, R. and Hegedűs, L. and Hegedűs, Tamás and Tóth, Sarolta and Papp, B. and Tordai, Attila and Enyedi, Ágnes}, doi = {10.1113/JP284179}, journal-iso = {J PHYSIOL-LONDON}, journal = {JOURNAL OF PHYSIOLOGY-LONDON}, volume = {602}, unique-id = {33731782}, issn = {0022-3751}, year = {2024}, eissn = {1469-7793}, pages = {1551-1564}, orcid-numbers = {Hegedűs, Tamás/0000-0002-0331-9629; Tóth, Sarolta/0000-0002-0341-7675; Tordai, Attila/0000-0001-6966-1622; Enyedi, Ágnes/0000-0002-7366-9376} } @article{MTMT:34879391, title = {Analysis of AlphaMissense data in different protein groups and structural context}, url = {https://m2.mtmt.hu/api/publication/34879391}, author = {Tordai, Hedvig and Torres Constante, Karen Odalys and Csepi, M. and Padányi, Rita and Lukács, G.L. and Hegedűs, Tamás}, doi = {10.1038/s41597-024-03327-8}, journal-iso = {SCI DATA}, journal = {SCIENTIFIC DATA}, volume = {11}, unique-id = {34879391}, year = {2024}, eissn = {2052-4463}, orcid-numbers = {Tordai, Hedvig/0000-0002-0875-5569; Torres Constante, Karen Odalys/0000-0002-7263-6425; Padányi, Rita/0000-0001-7798-0463; Hegedűs, Tamás/0000-0002-0331-9629} } @article{MTMT:35182006, title = {Synthesis and Biological Evaluation of Pyrazole-Pyrimidones as a New Class of Correctors of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)}, url = {https://m2.mtmt.hu/api/publication/35182006}, author = {Vaccarin, Christian and Veit, Guido and Hegedűs, Tamás and Torres Constante, Karen Odalys and Chilin, Adriana and Lukacs, Gergely L. and Marzaro, Giovanni}, doi = {10.1021/acs.jmedchem.4c00685}, journal-iso = {J MED CHEM}, journal = {JOURNAL OF MEDICINAL CHEMISTRY}, volume = {67}, unique-id = {35182006}, issn = {0022-2623}, abstract = {Cystic fibrosis (CF) is caused by the functional expression defect of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Despite the recent success in CFTR modulator development, the available correctors only partially restore the F508del-CFTR channel function, and several rare CF mutations show resistance to available drugs. We previously identified compound 4172 that synergistically rescued the F508del-CFTR folding defect in combination with the existing corrector drugs VX-809 and VX-661. Here, novel CFTR correctors were designed by applying a classical medicinal chemistry approach on the 4172 scaffold. Molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted to propose a plausible binding site and design more potent and effective analogs. We identified three optimized compounds, which, in combination with VX-809 and the investigational corrector 3151, increased the plasma membrane density and function of F508del-CFTR and other rare CFTR mutants resistant to the currently approved therapies.}, keywords = {MECHANISM; INHIBITORS; PROGRESS; lumacaftor; ivacaftor; CHARMM}, year = {2024}, eissn = {1520-4804}, pages = {13891-13908}, orcid-numbers = {Hegedűs, Tamás/0000-0002-0331-9629; Torres Constante, Karen Odalys/0000-0002-7263-6425} } @article{MTMT:34163279, title = {CoMemMoRFPred: Sequence-based Prediction of MemMoRFs by Combining Predictors of Intrinsic Disorder, MoRFs and Disordered Lipid-binding Regions}, url = {https://m2.mtmt.hu/api/publication/34163279}, author = {Basu, S. and Hegedűs, Tamás and Kurgan, L.}, doi = {10.1016/j.jmb.2023.168272}, journal-iso = {J MOL BIOL}, journal = {JOURNAL OF MOLECULAR BIOLOGY}, volume = {435}, unique-id = {34163279}, issn = {0022-2836}, year = {2023}, eissn = {1089-8638}, orcid-numbers = {Hegedűs, Tamás/0000-0002-0331-9629} } @article{MTMT:34175360, title = {Expression, Function and Trafficking of the Human ABCG2 Multidrug Transporter Containing Mutations in an Unstructured Cytoplasmic Loop}, url = {https://m2.mtmt.hu/api/publication/34175360}, author = {Mózner, Orsolya and Zámbó, Boglárka and Bartos, Zsuzsa and Gergely, Anna and Szabó, Kata Sára and Jezsó, Bálint and Telbisz, Ágnes Mária and Várady, György and Homolya, László and Hegedűs, Tamás and Sarkadi, Balázs}, doi = {10.3390/membranes13100822}, journal-iso = {MEMBRANES-BASEL}, journal = {MEMBRANES (BASEL)}, volume = {13}, unique-id = {34175360}, abstract = {The human ABCG2 multidrug transporter plays a crucial role in the absorption and excretion of xeno- and endobiotics, contributes to cancer drug resistance and the development of gout. In this work, we have analyzed the effects of selected variants, residing in a structurally unresolved cytoplasmic region (a.a. 354–367) of ABCG2 on the function and trafficking of this protein. A cluster of four lysines (K357–360) and the phosphorylation of a threonine (T362) residue in this region have been previously suggested to significantly affect the cellular fate of ABCG2. Here, we report that the naturally occurring K360del variant in human cells increased ABCG2 plasma membrane expression and accelerated cellular trafficking. The variable alanine replacements of the neighboring lysines had no significant effect on transport function, and the apical localization of ABCG2 in polarized cells has not been altered by any of these mutations. Moreover, in contrast to previous reports, we found that the phosphorylation-incompetent T362A, or the phosphorylation-mimicking T362E variants in this loop had no measurable effects on the function or expression of ABCG2. Molecular dynamics simulations indicated an increased mobility of the mutant variants with no major effects on the core structure of the protein. These results may help to decipher the potential role of this unstructured region within this transporter.}, year = {2023}, eissn = {2077-0375}, orcid-numbers = {Mózner, Orsolya/0000-0001-5784-7702; Bartos, Zsuzsa/0000-0001-9695-1422; Jezsó, Bálint/0000-0002-1306-4797; Telbisz, Ágnes Mária/0000-0003-0972-4606; Várady, György/0000-0003-2012-9680; Homolya, László/0000-0003-1639-8140; Hegedűs, Tamás/0000-0002-0331-9629; Sarkadi, Balázs/0000-0003-0592-4539} }