{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T06:52:21Z","timestamp":1773298341500,"version":"3.50.1"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"D1","license":[{"start":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003825","name":"Hungarian Academy of Sciences","doi-asserted-by":"publisher","award":["HAS-11015"],"award-info":[{"award-number":["HAS-11015"]}],"id":[{"id":"10.13039\/501100003825","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union's Horizon 2020 research and innovation program","award":["778247"],"award-info":[{"award-number":["778247"]}]},{"name":"European Union's Horizon 2020 research and innovation program","award":["952334"],"award-info":[{"award-number":["952334"]}]},{"name":"ELIXIR"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,1,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Fuzzy interactions are specific, variable contacts between proteins and other biomolecules (proteins, DNA, RNA, small molecules) formed in accord to the cellular context. Fuzzy interactions have recently been demonstrated to regulate biomolecular condensates generated by liquid-liquid phase separation. The FuzDB v4.0 database (https:\/\/fuzdb.org) assembles experimentally identified examples of fuzzy interactions, where disordered regions mediate functionally important, context-dependent contacts between the partners in stoichiometric and higher-order assemblies. The new version of FuzDB establishes cross-links with databases on structure (PDB, BMRB, PED), function (ELM, UniProt) and biomolecular condensates (PhaSepDB, PhaSePro, LLPSDB). FuzDB v4.0 is a source to decipher molecular basis of complex cellular interaction behaviors, including those in protein droplets.<\/jats:p>","DOI":"10.1093\/nar\/gkab1060","type":"journal-article","created":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T19:13:38Z","timestamp":1635362018000},"page":"D509-D517","source":"Crossref","is-referenced-by-count":50,"title":["FuzDB: a new phase in understanding fuzzy interactions"],"prefix":"10.1093","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9224-9820","authenticated-orcid":false,"given":"Andras","family":"Hatos","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58\/B, 35131 Padova, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0362-8218","authenticated-orcid":false,"given":"Alexander Miguel","family":"Monzon","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58\/B, 35131 Padova, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4525-7793","authenticated-orcid":false,"given":"Silvio C E","family":"Tosatto","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58\/B, 35131 Padova, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8210-2390","authenticated-orcid":false,"given":"Damiano","family":"Piovesan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58\/B, 35131 Padova, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4463-6727","authenticated-orcid":false,"given":"Monika","family":"Fuxreiter","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58\/B, 35131 Padova, Italy"},{"name":"Department of Biochemistry and Molecular Biology, University of Debrecen, Nagyerdei krt 98, 4010 Debrecen, Hungary"}]}],"member":"286","published-online":{"date-parts":[[2021,11,17]]},"reference":[{"key":"2022010507292341100_B1","doi-asserted-by":"crossref","first-page":"2278","DOI":"10.1016\/j.jmb.2018.02.015","article-title":"Fuzziness in protein interactions - a historical perspective","volume":"430","author":"Fuxreiter","year":"2018","journal-title":"J. Mol. Biol."},{"key":"2022010507292341100_B2","doi-asserted-by":"crossref","first-page":"3008","DOI":"10.3390\/molecules23113008","article-title":"Towards a stochastic paradigm: from fuzzy ensembles to cellular functions","volume":"23","author":"Fuxreiter","year":"2018","journal-title":"Molecules"},{"key":"2022010507292341100_B3","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.molcel.2012.05.039","article-title":"Tissue-specific splicing of disordered segments that embed binding motifs rewires protein interaction networks","volume":"46","author":"Buljan","year":"2012","journal-title":"Mol. Cell"},{"key":"2022010507292341100_B4","doi-asserted-by":"crossref","first-page":"e01998","DOI":"10.7554\/eLife.01998","article-title":"Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6","volume":"3","author":"Stamos","year":"2014","journal-title":"eLife"},{"key":"2022010507292341100_B5","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1002\/1873-3468.12762","article-title":"Fuzziness enables context dependence of protein interactions","volume":"591","author":"Miskei","year":"2017","journal-title":"FEBS Lett."},{"key":"2022010507292341100_B6","doi-asserted-by":"crossref","first-page":"3034","DOI":"10.1002\/cphc.201300387","article-title":"Conformational propensities of intrinsically disordered proteins from NMR chemical shifts","volume":"14","author":"Kragelj","year":"2013","journal-title":"ChemPhysChem"},{"key":"2022010507292341100_B7","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1002\/prot.23220","article-title":"Ensemble modeling of protein disordered states: experimental restraint contributions and validation","volume":"80","author":"Marsh","year":"2011","journal-title":"Proteins"},{"key":"2022010507292341100_B8","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.sbi.2018.10.006","article-title":"Determination of protein structural ensembles using cryo-electron microscopy","volume":"56","author":"Bonomi","year":"2019","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2022010507292341100_B9","doi-asserted-by":"crossref","first-page":"vi","DOI":"10.1016\/j.sbi.2019.06.006","article-title":"Dynamic protein interactions - from complexes to molecular machines","volume":"56","author":"Panchenko","year":"2019","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2022010507292341100_B10","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.tibs.2007.10.003","article-title":"Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions","volume":"33","author":"Tompa","year":"2008","journal-title":"Trends Biochem. Sci."},{"key":"2022010507292341100_B11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-4614-0659-4_1","article-title":"Fuzzy complexes: a more stochastic view of protein function","volume":"725","author":"Fuxreiter","year":"2012","journal-title":"Adv. Exp. Med. Biol."},{"key":"2022010507292341100_B12","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1039\/C1MB05234A","article-title":"Fuzziness: linking regulation to protein dynamics","volume":"8","author":"Fuxreiter","year":"2012","journal-title":"Mol. Biosyst."},{"key":"2022010507292341100_B13","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/j.cell.2016.05.004","article-title":"The structure and dynamics of higher-order assemblies: amyloids, signalosomes, and granules","volume":"165","author":"Wu","year":"2016","journal-title":"Cell"},{"key":"2022010507292341100_B14","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/s41556-021-00697-8","article-title":"Generic nature of the condensed states of proteins","volume":"23","author":"Fuxreiter","year":"2021","journal-title":"Nat. Cell Biol."},{"key":"2022010507292341100_B15","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nrm.2017.7","article-title":"Biomolecular condensates: organizers of cellular biochemistry","volume":"18","author":"Banani","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2022010507292341100_B16","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.tcb.2018.02.004","article-title":"Protein phase separation: a new phase in cell biology","volume":"28","author":"Boeynaems","year":"2018","journal-title":"Trends Cell Biol."},{"key":"2022010507292341100_B17","doi-asserted-by":"crossref","first-page":"E4408","DOI":"10.1073\/pnas.1701877114","article-title":"Direct observation of structure and dynamics during phase separation of an elastomeric protein","volume":"114","author":"Reichheld","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2022010507292341100_B18","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.molcel.2019.09.022","article-title":"Loss of dynamic RNA interaction and aberrant phase separation induced by two distinct types of ALS\/FTD-Linked FUS mutations","volume":"77","author":"Niaki","year":"2020","journal-title":"Mol. Cell"},{"key":"2022010507292341100_B19","doi-asserted-by":"crossref","first-page":"33254","DOI":"10.1073\/pnas.2007670117","article-title":"Widespread occurrence of the droplet state of proteins in the human proteome","volume":"117","author":"Hardenberg","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2022010507292341100_B20","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.cell.2013.01.033","article-title":"Dual specificity kinase DYRK3 couples stress granule condensation\/dissolution to mTORC1 signaling","volume":"152","author":"Wippich","year":"2013","journal-title":"Cell"},{"key":"2022010507292341100_B21","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/s41580-020-0264-6","article-title":"RNA contributions to the form and function of biomolecular condensates","volume":"22","author":"Roden","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2022010507292341100_B22","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1016\/j.cell.2018.10.042","article-title":"Transcription factors activate genes through the phase-separation capacity of their activation domains","volume":"175","author":"Boija","year":"2018","journal-title":"Cell"},{"key":"2022010507292341100_B23","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/s41580-020-00326-6","article-title":"Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing","volume":"22","author":"Alberti","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2022010507292341100_B24","doi-asserted-by":"crossref","first-page":"167201","DOI":"10.1016\/j.jmb.2021.167201","article-title":"Sequence determinants of the aggregation of proteins within condensates generated by liquid-liquid phase separation","author":"Vendruscolo","year":"2021","journal-title":"J. Mol. Biol."},{"key":"2022010507292341100_B25","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.sbi.2018.09.008","article-title":"Fold or not to fold upon binding - does it really matter?","volume":"54","author":"Fuxreiter","year":"2018","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2022010507292341100_B26","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nature13999","article-title":"Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch","volume":"519","author":"Bah","year":"2015","journal-title":"Nature"},{"key":"2022010507292341100_B27","doi-asserted-by":"crossref","first-page":"D228","DOI":"10.1093\/nar\/gkw1019","article-title":"FuzDB: database of fuzzy complexes, a tool to develop stochastic structure-function relationships for protein complexes and higher-order assemblies","volume":"45","author":"Miskei","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"2022010507292341100_B28","doi-asserted-by":"crossref","first-page":"8615","DOI":"10.3390\/ijms21228615","article-title":"Classifying the binding modes of disordered proteins","volume":"21","author":"Fuxreiter","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"2022010507292341100_B29","doi-asserted-by":"crossref","first-page":"e1007864","DOI":"10.1371\/journal.pcbi.1007864","article-title":"Sequence-based prediction of protein binding mode landscapes","volume":"16","author":"Horvath","year":"2020","journal-title":"PLoS Comp Biol"},{"key":"2022010507292341100_B30","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1016\/j.jmb.2020.02.017","article-title":"Sequence-based prediction of fuzzy protein interactions","volume":"432","author":"Miskei","year":"2020","journal-title":"J. Mol. Biol."},{"key":"2022010507292341100_B31","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"2022010507292341100_B32","doi-asserted-by":"crossref","first-page":"W367","DOI":"10.1093\/nar\/gkw315","article-title":"The RING 2.0 web server for high quality residue interaction networks","volume":"44","author":"Piovesan","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"2022010507292341100_B33","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1093\/bioinformatics\/btx592","article-title":"Mobi 2.0: an improved method to define intrinsic disorder, mobility and linear binding regions in protein structures","volume":"34","author":"Piovesan","year":"2018","journal-title":"Bioinformatics"},{"key":"2022010507292341100_B34","doi-asserted-by":"crossref","first-page":"D404","DOI":"10.1093\/nar\/gkaa1021","article-title":"PED in 2021: a major update of the protein ensemble database for intrinsically disordered proteins","volume":"49","author":"Lazar","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"2022010507292341100_B35","first-page":"D269","article-title":"DisProt: intrinsic protein disorder annotation in 2020","volume":"48","author":"Hatos","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"2022010507292341100_B36","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkaa1100","article-title":"UniProt: the universal protein knowledgebase in 2021","volume":"49","author":"UniProt","year":"2021","journal-title":"Nucleic. Acids. Res."},{"key":"2022010507292341100_B37","first-page":"D296","article-title":"ELM-the eukaryotic linear motif resource in 2020","volume":"48","author":"Kumar","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"2022010507292341100_B38","doi-asserted-by":"crossref","first-page":"D354","DOI":"10.1093\/nar\/gkz847","article-title":"PhaSepDB: a database of liquid-liquid phase separation related proteins","volume":"48","author":"You","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"2022010507292341100_B39","first-page":"D360","article-title":"PhaSePro: the database of proteins driving liquid-liquid phase separation","volume":"48","author":"Meszaros","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"2022010507292341100_B40","doi-asserted-by":"crossref","first-page":"D320","DOI":"10.1093\/nar\/gkz778","article-title":"LLPSDB: a database of proteins undergoing liquid-liquid phase separation in vitro","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"2022010507292341100_B41","doi-asserted-by":"crossref","first-page":"D412","DOI":"10.1093\/nar\/gkaa913","article-title":"Pfam: the protein families database in 2021","volume":"49","author":"Mistry","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"2022010507292341100_B42","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/bs.mie.2018.08.006","article-title":"Experimental characterization of fuzzy protein assemblies: interactions of paramyxoviral NTAIL domains with their functional partners","volume":"611","author":"Troilo","year":"2018","journal-title":"Methods Enzymol."},{"key":"2022010507292341100_B43","doi-asserted-by":"crossref","first-page":"e1007867","DOI":"10.1371\/journal.pcbi.1007867","article-title":"Balance between asymmetry and abundance in multi-domain DNA-binding proteins may regulate the kinetics of their binding to DNA","volume":"16","author":"Pal","year":"2020","journal-title":"PLoS Comput. Biol."},{"key":"2022010507292341100_B44","doi-asserted-by":"crossref","first-page":"W431","DOI":"10.1093\/nar\/gkab314","article-title":"Mol* Viewer: modern web app for 3D visualization and analysis of large biomolecular structures","volume":"49","author":"Sehnal","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"2022010507292341100_B45","doi-asserted-by":"crossref","first-page":"D402","DOI":"10.1093\/nar\/gkm957","article-title":"BioMagResBank","volume":"36","author":"Ulrich","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"2022010507292341100_B46","doi-asserted-by":"crossref","first-page":"6632","DOI":"10.1021\/cr400688u","article-title":"Exploring free-energy landscapes of intrinsically disordered proteins at atomic resolution using NMR spectroscopy","volume":"114","author":"Jensen","year":"2014","journal-title":"Chem. Rev."},{"key":"2022010507292341100_B47","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1002\/cbic.201200093","article-title":"Intrinsically disordered proteins: from sequence and conformational properties toward drug discovery","volume":"13","author":"Rezaei-Ghaleh","year":"2012","journal-title":"ChemBioChem"},{"key":"2022010507292341100_B48","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.jmb.2019.11.007","article-title":"Patterns of dynamics comprise a conserved evolutionary trait","volume":"432","author":"Zsolyomi","year":"2020","journal-title":"J. Mol. Biol."},{"key":"2022010507292341100_B49","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.molcel.2015.09.006","article-title":"Residue-by-residue view of in vitro FUS granules that bind the C-terminal domain of RNA polymerase II","volume":"60","author":"Burke","year":"2015","journal-title":"Mol. Cell"},{"key":"2022010507292341100_B50","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.sbi.2013.11.009","article-title":"Studying post-translational modifications with protein interaction networks","volume":"24","author":"Woodsmith","year":"2014","journal-title":"Curr. Opin. Struct. Biol."}],"container-title":["Nucleic Acids Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/50\/D1\/D509\/42057513\/gkab1060.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/50\/D1\/D509\/42057513\/gkab1060.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T07:43:37Z","timestamp":1641368617000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nar\/article\/50\/D1\/D509\/6430485"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,17]]},"references-count":50,"journal-issue":{"issue":"D1","published-online":{"date-parts":[[2021,11,17]]},"published-print":{"date-parts":[[2022,1,7]]}},"URL":"https:\/\/doi.org\/10.1093\/nar\/gkab1060","relation":{},"ISSN":["0305-1048","1362-4962"],"issn-type":[{"value":"0305-1048","type":"print"},{"value":"1362-4962","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,1,7]]},"published":{"date-parts":[[2021,11,17]]}}}