{ "types" : { "Bookmark" : { "pluralLabel" : "Bookmarks" }, "Publication" : { "pluralLabel" : "Publications" }, "GoldStandardPublication" : { "pluralLabel" : "GoldStandardPublications" }, "GoldStandardBookmark" : { "pluralLabel" : "GoldStandardBookmarks" }, "Tag" : { "pluralLabel" : "Tags" }, "User" : { "pluralLabel" : "Users" }, "Group" : { "pluralLabel" : "Groups" }, "Sphere" : { "pluralLabel" : "Spheres" } }, "properties" : { "count" : { "valueType" : "number" }, "date" : { "valueType" : "date" }, "changeDate" : { "valueType" : "date" }, "url" : { "valueType" : "url" }, "id" : { "valueType" : "url" }, "tags" : { "valueType" : "item" }, "user" : { "valueType" : "item" } }, "items" : [ { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/2090e8f7d3529477f0ee5f4494ab990f7/simtech", "tags" : [ "EXC2075","PN2","PN2-5","curated" ], "intraHash" : "090e8f7d3529477f0ee5f4494ab990f7", "interHash" : "7ca7381ffe7ca141c4443fe59a462873", "label" : "Mechanistic basis of the increased methylation activity of the SETD2 protein lysine methyltransferase towards a designed super-substrate peptide", "user" : "simtech", "description" : "", "date" : "2024-07-16 17:35:20", "changeDate" : "2024-07-19 15:09:42", "count" : 9, "pub-type": "article", "journal": "Communications Chemistry", "year": "2022", "url": "https://doi.org/10.1038/s42004-022-00753-w", "author": [ "Philipp Schnee","Michel Choudalakis","Sara Weirich","Mina S. Khella","Henrique Carvalho","Jürgen Pleiss","Albert Jeltsch" ], "authors": [ {"first" : "Philipp", "last" : "Schnee"}, {"first" : "Michel", "last" : "Choudalakis"}, {"first" : "Sara", "last" : "Weirich"}, {"first" : "Mina S.", "last" : "Khella"}, {"first" : "Henrique", "last" : "Carvalho"}, {"first" : "Jürgen", "last" : "Pleiss"}, {"first" : "Albert", "last" : "Jeltsch"} ], "volume": "5","number": "1","pages": "139--","abstract": "Protein lysine methyltransferases have important regulatory functions in cells, but mechanisms determining their activity and specificity are incompletely understood. Naturally, SETD2 introduces H3K36me3, but previously an artificial super-substrate (ssK36) was identified, which is methylated >100-fold faster. The ssK36-SETD2 complex structure cannot fully explain this effect. We applied molecular dynamics (MD) simulations and biochemical experiments to unravel the mechanistic basis of the increased methylation of ssK36, considering peptide conformations in solution, association of peptide and enzyme, and formation of transition-state (TS) like conformations of the enzyme-peptide complex. We observed in MD and FRET experiments that ssK36 adopts a hairpin conformation in solution with V35 and K36 placed in the loop. The hairpin conformation has easier access into the active site of SETD2 and it unfolds during the association process. Peptide methylation experiments revealed that introducing a stable hairpin conformation in the H3K36 peptide increased its methylation by SETD2. In MD simulations of enzyme-peptide complexes, the ssK36 peptide approached TS-like structures more frequently than H3K36 and distinct, substrate-specific TS-like structures were observed. Hairpin association, hairpin unfolding during association, and substrate-specific catalytically competent conformations may also be relevant for other PKMTs and hairpins could represent a promising starting point for SETD2 inhibitor development.", "orcid" : "0000-0003-1045-8202", "issn" : "23993669", "refid" : "Schnee2022", "doi" : "10.1038/s42004-022-00753-w", "bibtexKey": "schnee2022mechanistic" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/28da203b6974ed564e652588fd606d8e6/simtech", "tags" : [ "EXC2075","PN2","PN2-5","curated" ], "intraHash" : "8da203b6974ed564e652588fd606d8e6", "interHash" : "5cfde6ff2e0d4779533cad5bb4465b95", "label" : "The T1150A cancer mutant of the protein lysine dimethyltransferase NSD2 can introduce H3K36 trimethylation", "user" : "simtech", "description" : "", "date" : "2024-07-16 17:33:44", "changeDate" : "2024-08-09 07:50:50", "count" : 10, "pub-type": "article", "journal": "Journal of Biological Chemistry", "year": "2023", "url": "https://www.sciencedirect.com/science/article/pii/S0021925823018240", "author": [ "Mina S. Khella","Philipp Schnee","Sara Weirich","Tan Bui","Alexander Bröhm","Pavel Bashtrykov","Jürgen Pleiss","Albert Jeltsch" ], "authors": [ {"first" : "Mina S.", "last" : "Khella"}, {"first" : "Philipp", "last" : "Schnee"}, {"first" : "Sara", "last" : "Weirich"}, {"first" : "Tan", "last" : "Bui"}, {"first" : "Alexander", "last" : "Bröhm"}, {"first" : "Pavel", "last" : "Bashtrykov"}, {"first" : "Jürgen", "last" : "Pleiss"}, {"first" : "Albert", "last" : "Jeltsch"} ], "volume": "299","number": "6","pages": "104796--","abstract": "Protein lysine methyltransferases (PKMTs) play essential roles in gene expression regulation and cancer development. Somatic mutations in PKMTs are frequently observed in cancer cells. In biochemical experiments, we show here that the NSD1 mutations Y1971C, R2017Q, and R2017L observed mostly in solid cancers are catalytically inactive suggesting that NSD1 acts as a tumor suppressor gene in these tumors. In contrast, the frequently observed T1150A in NSD2 and its T2029A counterpart in NSD1, both observed in leukemia, are hyperactive and introduce up to three methyl groups in H3K36 in biochemical and cellular assays, while wildtype NSD2 and NSD1 only introduce up to two methyl groups. In Molecular Dynamics simulations, we determined key mechanistic and structural features controlling the product specificity of this class of enzymes. Simulations with NSD2 revealed that H3K36me3 formation is possible due to an enlarged active site pocket of T1150A and loss of direct contacts of T1150 to critical residues which regulate the product specificity of NSD2. Bioinformatic analyses of published data suggested that the generation of H3K36me3 by NSD2 T1150A could alter gene regulation by antagonizing H3K27me3 finally leading to the upregulation of oncogenes.", "orcid" : "0000-0003-1045-8202", "issn" : "00219258", "doi" : "https://doi.org/10.1016/j.jbc.2023.104796", "bibtexKey": "khella2023t1150a" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/2d9909ff847b9f217b69eea1ca56739f1/simtech", "tags" : [ "EXC2075","PN2","PN2-5","curated" ], "intraHash" : "d9909ff847b9f217b69eea1ca56739f1", "interHash" : "dc133ed70c9ecb61d411620750eb1d6a", "label" : "Approaching the catalytic mechanism of protein lysine methyltransferases by biochemical and simulation techniques", "user" : "simtech", "description" : "", "date" : "2024-07-16 17:32:47", "changeDate" : "2024-07-19 15:09:42", "count" : 7, "pub-type": "article", "journal": "Critical Reviews in Biochemistry and Molecular Biology","publisher":"Taylor & Francis", "year": "2024", "url": "https://doi.org/10.1080/10409238.2024.2318547 ", "author": [ "Philipp Schnee","Jürgen Pleiss","Albert Jeltsch" ], "authors": [ {"first" : "Philipp", "last" : "Schnee"}, {"first" : "Jürgen", "last" : "Pleiss"}, {"first" : "Albert", "last" : "Jeltsch"} ], "volume": "59","number": "1-2","pages": "20-68", "orcid" : "0000-0003-1045-8202", "eprint" : "https://doi.org/10.1080/10409238.2024.2318547", "doi" : "10.1080/10409238.2024.2318547", "bibtexKey": "doi:10.1080/10409238.2024.2318547" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/272af99c797370695f57647c06fb10429/simtech", "tags" : [ "EXC2075","PN2","PN2-5","curated" ], "intraHash" : "72af99c797370695f57647c06fb10429", "interHash" : "08a87a4b59f0eec9105c21ec6be71ee4", "label" : "Discovery of NSD2 non-histone substrates and design of a super-substrate", "user" : "simtech", "description" : "", "date" : "2024-07-16 17:28:05", "changeDate" : "2025-01-27 13:14:14", "count" : 7, "pub-type": "article", "journal": "Communications Biology", "year": "2024", "url": "https://doi.org/10.1038/s42003-024-06395-z", "author": [ "Sara Weirich","Denis Kusevic","Philipp Schnee","Jessica Reiter","Jürgen Pleiss","Albert Jeltsch" ], "authors": [ {"first" : "Sara", "last" : "Weirich"}, {"first" : "Denis", "last" : "Kusevic"}, {"first" : "Philipp", "last" : "Schnee"}, {"first" : "Jessica", "last" : "Reiter"}, {"first" : "Jürgen", "last" : "Pleiss"}, {"first" : "Albert", "last" : "Jeltsch"} ], "volume": "7","number": "1","pages": "707--","abstract": "The human protein lysine methyltransferase NSD2 catalyzes dimethylation at H3K36. It has very important roles in development and disease but many mechanistic features and its full spectrum of substrate proteins are unclear. Using peptide SPOT array methylation assays, we investigate the substrate sequence specificity of NSD2 and discover strong readout of residues between G33 (-3) and P38 (+2) on H3K36. Unexpectedly, we observe that amino acid residues different from natural ones in H3K36 are preferred at some positions. Combining four preferred residues led to the development of a super-substrate which is methylated much faster by NSD2 at peptide and protein level. Molecular dynamics simulations demonstrate that this activity increase is caused by distinct hyperactive conformations of the enzyme-peptide complex. To investigate the substrate spectrum of NSD2, we conducted a proteome wide search for nuclear proteins matching the specificity profile and discovered 22 peptide substrates of NSD2. In protein methylation studies, we identify K1033 of ATRX and K819 of FANCM as NSD2 methylation sites and also demonstrate their methylation in human cells. Both these proteins have important roles in DNA repair strengthening the connection of NSD2 and H3K36 methylation to DNA repair.", "orcid" : "0000-0003-1045-8202", "issn" : "23993642", "refid" : "Weirich2024", "doi" : "10.1038/s42003-024-06395-z", "bibtexKey": "weirich2024discovery" } , { "type" : "Publication", "id" : "https://puma.ub.uni-stuttgart.de/bibtex/2da7e5780849a625563e81173cd58d8af/simtech", "tags" : [ "EXC2075","PN2","PN2-5","PN2-6","PN2-6(II)","curated" ], "intraHash" : "da7e5780849a625563e81173cd58d8af", "interHash" : "f1c9dcbbef1bbfe5bfb78cb5e44fd71a", "label" : "Preferential Self-interaction of DNA Methyltransferase DNMT3A Subunits Containing the R882H Cancer Mutation Leads to Dominant Changes of Flanking Sequence Preferences", "user" : "simtech", "description" : "", "date" : "2023-11-15 17:28:32", "changeDate" : "2024-07-17 11:43:17", "count" : 15, "pub-type": "article", "journal": "Journal of Molecular Biology","publisher":"Elsevier BV", "year": "2022", "url": "https://doi.org/10.1016%2Fj.jmb.2022.167482", "author": [ "Alexandra Mack","Max Emperle","Philipp Schnee","Sabrina Adam","Jürgen Pleiss","Pavel Bashtrykov","Albert Jeltsch" ], "authors": [ {"first" : "Alexandra", "last" : "Mack"}, {"first" : "Max", "last" : "Emperle"}, {"first" : "Philipp", "last" : "Schnee"}, {"first" : "Sabrina", "last" : "Adam"}, {"first" : "Jürgen", "last" : "Pleiss"}, {"first" : "Pavel", "last" : "Bashtrykov"}, {"first" : "Albert", "last" : "Jeltsch"} ], "volume": "434","number": "7","pages": "167482", "doi" : "10.1016/j.jmb.2022.167482", "bibtexKey": "Mack_2022" } ] }