Coupled structural transitions enable highly cooperative regulation of human CTPS2 filaments
Many enzymes assemble into defined oligomers, providing a mechanism for cooperatively regulating activity. Recent studies have described a mode of regulation in which enzyme activity is modulated by polymerization into large-scale filaments. Here we describe an ultrasensitive form of polymerization-...
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| Veröffentlicht in: | Nature structural & molecular biology 2020-01, Vol.27 (1), p.42-48 |
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| description | Many enzymes assemble into defined oligomers, providing a mechanism for cooperatively regulating activity. Recent studies have described a mode of regulation in which enzyme activity is modulated by polymerization into large-scale filaments. Here we describe an ultrasensitive form of polymerization-based regulation employed by human CTP synthase 2 (CTPS2). Cryo-EM structures reveal that CTPS2 filaments dynamically switch between active and inactive forms in response to changes in substrate and product levels. Linking the conformational state of many CTPS2 subunits in a filament results in highly cooperative regulation, greatly exceeding the limits of cooperativity for the CTPS2 tetramer alone. The structures reveal a link between conformation and control of ammonia channeling between the enzyme’s active sites, and explain differences in regulation of human CTPS isoforms. This filament-based mechanism of enhanced cooperativity demonstrates how the widespread phenomenon of enzyme polymerization can be adapted to achieve different regulatory outcomes.
Cryo-EM and functional analyses of human CTP synthase 2 reveal that this enzyme forms polymeric filaments that can switch between active and inactive forms, in response to substrate and product levels, resulting in highly cooperative regulation. |
| doi_str_mv | 10.1038/s41594-019-0352-5 |
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Cryo-EM and functional analyses of human CTP synthase 2 reveal that this enzyme forms polymeric filaments that can switch between active and inactive forms, in response to substrate and product levels, resulting in highly cooperative regulation.</description><identifier>ISSN: 1545-9993</identifier><identifier>EISSN: 1545-9985</identifier><identifier>DOI: 10.1038/s41594-019-0352-5</identifier><identifier>PMID: 31873303</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>101/28 ; 631/45/607 ; 631/535/1258/1259 ; Ammonia ; Biochemistry ; Biological Microscopy ; Biomedical and Life Sciences ; Carbon-Nitrogen Ligases - chemistry ; Carbon-Nitrogen Ligases - metabolism ; Carbon-Nitrogen Ligases - ultrastructure ; Catalytic Domain ; Channeling ; Conformation ; Cooperativity ; Cryoelectron Microscopy ; CTP synthase ; Enzymatic activity ; Enzyme Activation ; Enzyme activity ; Enzymes ; Filaments ; Genetic regulation ; Genetic research ; Humans ; Isoforms ; Life Sciences ; Membrane Biology ; Models, Molecular ; Oligomers ; Polymerization ; Protein Conformation ; Protein Multimerization ; Protein Structure ; Proteins ; Structure ; Substrate Specificity ; Substrates</subject><ispartof>Nature structural & molecular biology, 2020-01, Vol.27 (1), p.42-48</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2019</rights><rights>COPYRIGHT 2020 Nature Publishing Group</rights><rights>2019© The Author(s), under exclusive licence to Springer Nature America, Inc. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c571t-5663e4f57f0f4f6dfb481bff6ac267aab0eceb79db784d82b5b2954532f4f5453</citedby><cites>FETCH-LOGICAL-c571t-5663e4f57f0f4f6dfb481bff6ac267aab0eceb79db784d82b5b2954532f4f5453</cites><orcidid>0000-0001-5897-5167 ; 0000-0002-0350-5827</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41594-019-0352-5$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41594-019-0352-5$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,27923,27924,41487,42556,51318</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31873303$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lynch, Eric M.</creatorcontrib><creatorcontrib>Kollman, Justin M.</creatorcontrib><title>Coupled structural transitions enable highly cooperative regulation of human CTPS2 filaments</title><title>Nature structural & molecular biology</title><addtitle>Nat Struct Mol Biol</addtitle><addtitle>Nat Struct Mol Biol</addtitle><description>Many enzymes assemble into defined oligomers, providing a mechanism for cooperatively regulating activity. Recent studies have described a mode of regulation in which enzyme activity is modulated by polymerization into large-scale filaments. Here we describe an ultrasensitive form of polymerization-based regulation employed by human CTP synthase 2 (CTPS2). Cryo-EM structures reveal that CTPS2 filaments dynamically switch between active and inactive forms in response to changes in substrate and product levels. Linking the conformational state of many CTPS2 subunits in a filament results in highly cooperative regulation, greatly exceeding the limits of cooperativity for the CTPS2 tetramer alone. The structures reveal a link between conformation and control of ammonia channeling between the enzyme’s active sites, and explain differences in regulation of human CTPS isoforms. This filament-based mechanism of enhanced cooperativity demonstrates how the widespread phenomenon of enzyme polymerization can be adapted to achieve different regulatory outcomes.
Cryo-EM and functional analyses of human CTP synthase 2 reveal that this enzyme forms polymeric filaments that can switch between active and inactive forms, in response to substrate and product levels, resulting in highly cooperative regulation.</description><subject>101/28</subject><subject>631/45/607</subject><subject>631/535/1258/1259</subject><subject>Ammonia</subject><subject>Biochemistry</subject><subject>Biological Microscopy</subject><subject>Biomedical and Life Sciences</subject><subject>Carbon-Nitrogen Ligases - chemistry</subject><subject>Carbon-Nitrogen Ligases - metabolism</subject><subject>Carbon-Nitrogen Ligases - ultrastructure</subject><subject>Catalytic Domain</subject><subject>Channeling</subject><subject>Conformation</subject><subject>Cooperativity</subject><subject>Cryoelectron Microscopy</subject><subject>CTP synthase</subject><subject>Enzymatic activity</subject><subject>Enzyme Activation</subject><subject>Enzyme activity</subject><subject>Enzymes</subject><subject>Filaments</subject><subject>Genetic regulation</subject><subject>Genetic research</subject><subject>Humans</subject><subject>Isoforms</subject><subject>Life Sciences</subject><subject>Membrane Biology</subject><subject>Models, Molecular</subject><subject>Oligomers</subject><subject>Polymerization</subject><subject>Protein Conformation</subject><subject>Protein Multimerization</subject><subject>Protein Structure</subject><subject>Proteins</subject><subject>Structure</subject><subject>Substrate Specificity</subject><subject>Substrates</subject><issn>1545-9993</issn><issn>1545-9985</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1kltrFTEUhQdR7EV_gC8y4Ev7MDWXyczkRSgHq4WCYuubEDKZnTkpM8kxl2L_fTOceuoRJYEE9rfXZi9WUbzB6Awj2r0PNWa8rhDmFaKMVOxZcYhZzSrOO_Z89-f0oDgK4RYhwlhLXxYHFHctpYgeFj9WLm0mGMoQfVIxeTmV0UsbTDTOhhKs7Cco12ZcT_elcm4DXkZzB6WHMU1yoUqny3WapS1XN1-vSanNJGewMbwqXmg5BXj9-B4X3y8-3qw-V1dfPl2uzq8qxVocK9Y0FGrNWo10rZtB93WHe60bqUjTStkjUNC3fOjbrh460rOe8LwaJRlf3uPiw1Z3k_oZBpVn5z3ExptZ-nvhpBH7FWvWYnR3osky-WaBk0cB734mCFHMJiiYJmnBpSDIYhbNA3FG3_2F3rrkbV4vUzWhLce4e6JGOYEwVrs8Vy2i4rzBGNW84Qt19g8qnwFmo5yF7CTsN5zuNWQmwq84yhSCuLz-ts_iLau8C8GD3vmBkVjiI7bxETk-YomPWIx8-6eRu47feckA2QIhl-wI_mn7_6s-AAQmz8c</recordid><startdate>20200101</startdate><enddate>20200101</enddate><creator>Lynch, Eric M.</creator><creator>Kollman, Justin M.</creator><general>Nature Publishing Group US</general><general>Nature Publishing Group</general><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>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PADUT</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5897-5167</orcidid><orcidid>https://orcid.org/0000-0002-0350-5827</orcidid></search><sort><creationdate>20200101</creationdate><title>Coupled structural transitions enable highly cooperative regulation of human CTPS2 filaments</title><author>Lynch, Eric M. ; Kollman, Justin M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c571t-5663e4f57f0f4f6dfb481bff6ac267aab0eceb79db784d82b5b2954532f4f5453</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>101/28</topic><topic>631/45/607</topic><topic>631/535/1258/1259</topic><topic>Ammonia</topic><topic>Biochemistry</topic><topic>Biological Microscopy</topic><topic>Biomedical and Life Sciences</topic><topic>Carbon-Nitrogen Ligases - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature structural & molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lynch, Eric M.</au><au>Kollman, Justin M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Coupled structural transitions enable highly cooperative regulation of human CTPS2 filaments</atitle><jtitle>Nature structural & molecular biology</jtitle><stitle>Nat Struct Mol Biol</stitle><addtitle>Nat Struct Mol Biol</addtitle><date>2020-01-01</date><risdate>2020</risdate><volume>27</volume><issue>1</issue><spage>42</spage><epage>48</epage><pages>42-48</pages><issn>1545-9993</issn><eissn>1545-9985</eissn><abstract>Many enzymes assemble into defined oligomers, providing a mechanism for cooperatively regulating activity. Recent studies have described a mode of regulation in which enzyme activity is modulated by polymerization into large-scale filaments. Here we describe an ultrasensitive form of polymerization-based regulation employed by human CTP synthase 2 (CTPS2). Cryo-EM structures reveal that CTPS2 filaments dynamically switch between active and inactive forms in response to changes in substrate and product levels. Linking the conformational state of many CTPS2 subunits in a filament results in highly cooperative regulation, greatly exceeding the limits of cooperativity for the CTPS2 tetramer alone. The structures reveal a link between conformation and control of ammonia channeling between the enzyme’s active sites, and explain differences in regulation of human CTPS isoforms. This filament-based mechanism of enhanced cooperativity demonstrates how the widespread phenomenon of enzyme polymerization can be adapted to achieve different regulatory outcomes.
Cryo-EM and functional analyses of human CTP synthase 2 reveal that this enzyme forms polymeric filaments that can switch between active and inactive forms, in response to substrate and product levels, resulting in highly cooperative regulation.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>31873303</pmid><doi>10.1038/s41594-019-0352-5</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0001-5897-5167</orcidid><orcidid>https://orcid.org/0000-0002-0350-5827</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 101/28 631/45/607 631/535/1258/1259 Ammonia Biochemistry Biological Microscopy Biomedical and Life Sciences Carbon-Nitrogen Ligases - chemistry Carbon-Nitrogen Ligases - metabolism Carbon-Nitrogen Ligases - ultrastructure Catalytic Domain Channeling Conformation Cooperativity Cryoelectron Microscopy CTP synthase Enzymatic activity Enzyme Activation Enzyme activity Enzymes Filaments Genetic regulation Genetic research Humans Isoforms Life Sciences Membrane Biology Models, Molecular Oligomers Polymerization Protein Conformation Protein Multimerization Protein Structure Proteins Structure Substrate Specificity Substrates |
| title | Coupled structural transitions enable highly cooperative regulation of human CTPS2 filaments |
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