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Histidine methyltransferase SETD3 methylates structurally diverse histidine mimics in actin
Actin histidine Nτ‐methylation by histidine methyltransferase SETD3 plays an important role in human biology and diseases. Here, we report integrated synthetic, biocatalytic, biostructural, and computational analyses on human SETD3‐catalyzed methylation of actin peptides possessing histidine and its...
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| Published in: | Protein science 2022-05, Vol.31 (5), p.e4305-n/a |
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| container_title | Protein science |
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| creator | Hintzen, Jordi C. J. Ma, Huida Deng, Hao Witecka, Apolonia Andersen, Steffen B. Drozak, Jakub Guo, Hong Qian, Ping Li, Haitao Mecinović, Jasmin |
| description | Actin histidine Nτ‐methylation by histidine methyltransferase SETD3 plays an important role in human biology and diseases. Here, we report integrated synthetic, biocatalytic, biostructural, and computational analyses on human SETD3‐catalyzed methylation of actin peptides possessing histidine and its structurally and chemically diverse mimics. Our enzyme assays supported by biostructural analyses demonstrate that SETD3 has a broader substrate scope beyond histidine, including N‐nucleophiles on the aromatic and aliphatic side chains. Quantum mechanical/molecular mechanical molecular dynamics and free‐energy simulations provide insight into binding geometries and the free energy barrier for the enzymatic methyl transfer to histidine mimics, further supporting experimental data that histidine is the superior SETD3 substrate over its analogs. This work demonstrates that human SETD3 has a potential to catalyze efficient methylation of several histidine mimics, overall providing mechanistic, biocatalytic, and functional insight into actin histidine methylation by SETD3.
PDB Code(s): 7W28 and 7W29 |
| doi_str_mv | 10.1002/pro.4305 |
| format | article |
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PDB Code(s): 7W28 and 7W29</description><identifier>ISSN: 0961-8368</identifier><identifier>ISSN: 1469-896X</identifier><identifier>EISSN: 1469-896X</identifier><identifier>DOI: 10.1002/pro.4305</identifier><identifier>PMID: 35481649</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>Actin ; Actins - chemistry ; Actins - metabolism ; biocatalysis ; Computer applications ; Free energy ; Full‐length Paper ; Full‐length Papers ; Histidine ; Histidine - chemistry ; Histone Methyltransferases - chemistry ; Histone Methyltransferases - metabolism ; Humans ; Methylation ; Methyltransferase ; Methyltransferases - metabolism ; Molecular chains ; Molecular dynamics ; Nucleophiles ; Peptides ; Quantum mechanics ; SETD3 ; Substrates ; β‐actin</subject><ispartof>Protein science, 2022-05, Vol.31 (5), p.e4305-n/a</ispartof><rights>2022 The Authors. published by Wiley Periodicals LLC on behalf of The Protein Society.</rights><rights>2022 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.</rights><rights>2022. This article is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4385-bd3010cb5f1381c4f78e9440899134eb39d242e95567f09b89d5bd3b60a5e8673</citedby><cites>FETCH-LOGICAL-c4385-bd3010cb5f1381c4f78e9440899134eb39d242e95567f09b89d5bd3b60a5e8673</cites><orcidid>0000-0002-5559-3822</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fpro.4305$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fpro.4305$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,50923,51032,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35481649$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hintzen, Jordi C. J.</creatorcontrib><creatorcontrib>Ma, Huida</creatorcontrib><creatorcontrib>Deng, Hao</creatorcontrib><creatorcontrib>Witecka, Apolonia</creatorcontrib><creatorcontrib>Andersen, Steffen B.</creatorcontrib><creatorcontrib>Drozak, Jakub</creatorcontrib><creatorcontrib>Guo, Hong</creatorcontrib><creatorcontrib>Qian, Ping</creatorcontrib><creatorcontrib>Li, Haitao</creatorcontrib><creatorcontrib>Mecinović, Jasmin</creatorcontrib><title>Histidine methyltransferase SETD3 methylates structurally diverse histidine mimics in actin</title><title>Protein science</title><addtitle>Protein Sci</addtitle><description>Actin histidine Nτ‐methylation by histidine methyltransferase SETD3 plays an important role in human biology and diseases. Here, we report integrated synthetic, biocatalytic, biostructural, and computational analyses on human SETD3‐catalyzed methylation of actin peptides possessing histidine and its structurally and chemically diverse mimics. Our enzyme assays supported by biostructural analyses demonstrate that SETD3 has a broader substrate scope beyond histidine, including N‐nucleophiles on the aromatic and aliphatic side chains. Quantum mechanical/molecular mechanical molecular dynamics and free‐energy simulations provide insight into binding geometries and the free energy barrier for the enzymatic methyl transfer to histidine mimics, further supporting experimental data that histidine is the superior SETD3 substrate over its analogs. This work demonstrates that human SETD3 has a potential to catalyze efficient methylation of several histidine mimics, overall providing mechanistic, biocatalytic, and functional insight into actin histidine methylation by SETD3.
PDB Code(s): 7W28 and 7W29</description><subject>Actin</subject><subject>Actins - chemistry</subject><subject>Actins - metabolism</subject><subject>biocatalysis</subject><subject>Computer applications</subject><subject>Free energy</subject><subject>Full‐length Paper</subject><subject>Full‐length Papers</subject><subject>Histidine</subject><subject>Histidine - chemistry</subject><subject>Histone Methyltransferases - chemistry</subject><subject>Histone Methyltransferases - metabolism</subject><subject>Humans</subject><subject>Methylation</subject><subject>Methyltransferase</subject><subject>Methyltransferases - metabolism</subject><subject>Molecular chains</subject><subject>Molecular dynamics</subject><subject>Nucleophiles</subject><subject>Peptides</subject><subject>Quantum mechanics</subject><subject>SETD3</subject><subject>Substrates</subject><subject>β‐actin</subject><issn>0961-8368</issn><issn>1469-896X</issn><issn>1469-896X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><recordid>eNp1kclKBDEQhoMoOi7gE0iDFy89Jp1lkosg4zKCoLiA4CGk09VOpJcx6Vbm7Y06ruApJPnyVVV-hLYJHhKMs_2Zb4eMYr6EBoQJlUol7pbRACtBUkmFXEPrITxijBnJ6Cpao5xJIpgaoPuJC50rXANJDd10XnXeNKEEbwIk18c3R3RxbjoISeh8b7vem6qaJ4V7Bh-p6bfB1c6GxDWJsZ1rNtFKaaoAW4t1A92eHN-MJ-n5xenZ-PA8tYxKnuYFxQTbnJeESmJZOZKgGMNSKUIZ5FQVGctAcS5GJVa5VAWPb3KBDQcpRnQDHXx4Z31eQ2GhiUNUeuZdbfxct8bp3zeNm-qH9lmr-CEZY1GwtxD49qmH0OnaBQtVZRpo-6AzEUtzwUY8ort_0Me2900c753CCtNMfQutb0PwUH41Q7B-SyzuW_2WWER3fjb_BX5GFIH0A3hxFcz_FenLq4t34SsvkaDg</recordid><startdate>202205</startdate><enddate>202205</enddate><creator>Hintzen, Jordi C. J.</creator><creator>Ma, Huida</creator><creator>Deng, Hao</creator><creator>Witecka, Apolonia</creator><creator>Andersen, Steffen B.</creator><creator>Drozak, Jakub</creator><creator>Guo, Hong</creator><creator>Qian, Ping</creator><creator>Li, Haitao</creator><creator>Mecinović, Jasmin</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7T5</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5559-3822</orcidid></search><sort><creationdate>202205</creationdate><title>Histidine methyltransferase SETD3 methylates structurally diverse histidine mimics in actin</title><author>Hintzen, Jordi C. J. ; Ma, Huida ; Deng, Hao ; Witecka, Apolonia ; Andersen, Steffen B. ; Drozak, Jakub ; Guo, Hong ; Qian, Ping ; Li, Haitao ; Mecinović, Jasmin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4385-bd3010cb5f1381c4f78e9440899134eb39d242e95567f09b89d5bd3b60a5e8673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Actin</topic><topic>Actins - chemistry</topic><topic>Actins - metabolism</topic><topic>biocatalysis</topic><topic>Computer applications</topic><topic>Free energy</topic><topic>Full‐length Paper</topic><topic>Full‐length Papers</topic><topic>Histidine</topic><topic>Histidine - chemistry</topic><topic>Histone Methyltransferases - chemistry</topic><topic>Histone Methyltransferases - metabolism</topic><topic>Humans</topic><topic>Methylation</topic><topic>Methyltransferase</topic><topic>Methyltransferases - metabolism</topic><topic>Molecular chains</topic><topic>Molecular dynamics</topic><topic>Nucleophiles</topic><topic>Peptides</topic><topic>Quantum mechanics</topic><topic>SETD3</topic><topic>Substrates</topic><topic>β‐actin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hintzen, Jordi C. J.</creatorcontrib><creatorcontrib>Ma, Huida</creatorcontrib><creatorcontrib>Deng, Hao</creatorcontrib><creatorcontrib>Witecka, Apolonia</creatorcontrib><creatorcontrib>Andersen, Steffen B.</creatorcontrib><creatorcontrib>Drozak, Jakub</creatorcontrib><creatorcontrib>Guo, Hong</creatorcontrib><creatorcontrib>Qian, Ping</creatorcontrib><creatorcontrib>Li, Haitao</creatorcontrib><creatorcontrib>Mecinović, Jasmin</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Online Library Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Protein science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hintzen, Jordi C. J.</au><au>Ma, Huida</au><au>Deng, Hao</au><au>Witecka, Apolonia</au><au>Andersen, Steffen B.</au><au>Drozak, Jakub</au><au>Guo, Hong</au><au>Qian, Ping</au><au>Li, Haitao</au><au>Mecinović, Jasmin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Histidine methyltransferase SETD3 methylates structurally diverse histidine mimics in actin</atitle><jtitle>Protein science</jtitle><addtitle>Protein Sci</addtitle><date>2022-05</date><risdate>2022</risdate><volume>31</volume><issue>5</issue><spage>e4305</spage><epage>n/a</epage><pages>e4305-n/a</pages><issn>0961-8368</issn><issn>1469-896X</issn><eissn>1469-896X</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Review Editor: John Kuriyan</notes><notes>Jordi C. J. Hintzen, Huida Ma, and Hao Deng contributed equally to this study.</notes><notes>Funding information H2020 European Research Council, Grant/Award Number: 715691; Narodowe Centrum Nauki, Grant/Award Number: 2017/27/B/NZ1/00161; National Natural Science Foundation of China, Grant/Award Numbers: 22177064, 31725014; Natural Science Foundation of Shandong Province, Grant/Award Number: ZR2021MB050; National Key Research Development Program of China, Grant/Award Number: 2020YFA0803300</notes><abstract>Actin histidine Nτ‐methylation by histidine methyltransferase SETD3 plays an important role in human biology and diseases. Here, we report integrated synthetic, biocatalytic, biostructural, and computational analyses on human SETD3‐catalyzed methylation of actin peptides possessing histidine and its structurally and chemically diverse mimics. Our enzyme assays supported by biostructural analyses demonstrate that SETD3 has a broader substrate scope beyond histidine, including N‐nucleophiles on the aromatic and aliphatic side chains. Quantum mechanical/molecular mechanical molecular dynamics and free‐energy simulations provide insight into binding geometries and the free energy barrier for the enzymatic methyl transfer to histidine mimics, further supporting experimental data that histidine is the superior SETD3 substrate over its analogs. This work demonstrates that human SETD3 has a potential to catalyze efficient methylation of several histidine mimics, overall providing mechanistic, biocatalytic, and functional insight into actin histidine methylation by SETD3.
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| source | Wiley-Blackwell Journals; PubMed Central |
| subjects | Actin Actins - chemistry Actins - metabolism biocatalysis Computer applications Free energy Full‐length Paper Full‐length Papers Histidine Histidine - chemistry Histone Methyltransferases - chemistry Histone Methyltransferases - metabolism Humans Methylation Methyltransferase Methyltransferases - metabolism Molecular chains Molecular dynamics Nucleophiles Peptides Quantum mechanics SETD3 Substrates β‐actin |
| title | Histidine methyltransferase SETD3 methylates structurally diverse histidine mimics in actin |
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