Molecular interactions underlying liquid−liquid phase separation of the FUS low-complexity domain
The low-complexity domain of the RNA-binding protein FUS (FUS LC) mediates liquid−liquid phase separation (LLPS), but the interactions between the repetitive SYGQ-rich sequence of FUS LC that stabilize the liquid phase are not known in detail. By combining NMR and Raman spectroscopy, mutagenesis, an...
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| Veröffentlicht in: | Nature structural & molecular biology 2019-07, Vol.26 (7), p.637-648 |
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| creator | Murthy, Anastasia C. Dignon, Gregory L. Kan, Yelena Zerze, Gül H. Parekh, Sapun H. Mittal, Jeetain Fawzi, Nicolas L. |
| description | The low-complexity domain of the RNA-binding protein FUS (FUS LC) mediates liquid−liquid phase separation (LLPS), but the interactions between the repetitive SYGQ-rich sequence of FUS LC that stabilize the liquid phase are not known in detail. By combining NMR and Raman spectroscopy, mutagenesis, and molecular simulation, we demonstrate that heterogeneous interactions involving all residue types underlie LLPS of human FUS LC. We find no evidence that FUS LC adopts conformations with traditional secondary structure elements in the condensed phase; rather, it maintains conformational heterogeneity. We show that hydrogen bonding, π/sp
2
, and hydrophobic interactions all contribute to stabilizing LLPS of FUS LC. In addition to contributions from tyrosine residues, we find that glutamine residues also participate in contacts leading to LLPS of FUS LC. These results support a model in which FUS LC forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.
The low-complexity domain of the RNA-binding protein FUS forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase. |
| doi_str_mv | 10.1038/s41594-019-0250-x |
| format | Article |
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2
, and hydrophobic interactions all contribute to stabilizing LLPS of FUS LC. In addition to contributions from tyrosine residues, we find that glutamine residues also participate in contacts leading to LLPS of FUS LC. These results support a model in which FUS LC forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.
The low-complexity domain of the RNA-binding protein FUS forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.</description><identifier>ISSN: 1545-9993</identifier><identifier>EISSN: 1545-9985</identifier><identifier>DOI: 10.1038/s41594-019-0250-x</identifier><identifier>PMID: 31270472</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/45/535/878 ; 631/45/535/878/1263 ; 631/57/2269 ; BASIC BIOLOGICAL SCIENCES ; Biochemistry ; Biological Microscopy ; Biomedical and Life Sciences ; Chemical properties ; Compartmental analysis (Biology) ; Complexity ; Composition ; Computer simulation ; Engineering ; FUS protein ; Glutamine ; Health aspects ; Heterogeneity ; Humans ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Hydrophobicity ; Intrinsically disordered proteins ; Intrinsically Disordered Proteins - chemistry ; Life Sciences ; Liquid phases ; Macromolecules ; Membrane Biology ; Models, Molecular ; Molecular biology ; Molecular interactions ; Mutagenesis ; NMR ; NMR spectroscopy ; Nuclear magnetic resonance ; Phase separation ; Phase transformations (Statistical physics) ; Phase Transition ; Polypeptides ; Protein Conformation ; Protein Domains ; Protein research ; Protein Structure ; Protein Structure, Secondary ; Proteins ; Raman spectroscopy ; Residues ; Ribonucleic acid ; RNA ; RNA polymerase ; RNA-binding protein ; RNA-Binding Protein FUS - chemistry ; Secondary structure ; solution-state NMR ; Spectrum analysis ; Transcription factors ; Tyrosine</subject><ispartof>Nature structural & molecular biology, 2019-07, Vol.26 (7), p.637-648</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2019</rights><rights>COPYRIGHT 2019 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c664t-51e2820b99c01b295190ecddcc9c7a3b8e13ade09adeefbe7a09b09ace25bdc03</citedby><cites>FETCH-LOGICAL-c664t-51e2820b99c01b295190ecddcc9c7a3b8e13ade09adeefbe7a09b09ace25bdc03</cites><orcidid>0000-0001-8522-1854 ; 0000-0002-2490-697X ; 0000-0002-9725-6402 ; 0000-0001-8016-8652 ; 0000-0001-5483-0577 ; 0000000297256402 ; 0000000185221854 ; 0000000180168652 ; 000000022490697X ; 0000000154830577</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/s41594-019-0250-x$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41594-019-0250-x$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31270472$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/servlets/purl/1577559$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Murthy, Anastasia C.</creatorcontrib><creatorcontrib>Dignon, Gregory L.</creatorcontrib><creatorcontrib>Kan, Yelena</creatorcontrib><creatorcontrib>Zerze, Gül H.</creatorcontrib><creatorcontrib>Parekh, Sapun H.</creatorcontrib><creatorcontrib>Mittal, Jeetain</creatorcontrib><creatorcontrib>Fawzi, Nicolas L.</creatorcontrib><creatorcontrib>Lehigh Univ., Bethlehem, PA (United States)</creatorcontrib><creatorcontrib>Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)</creatorcontrib><title>Molecular interactions underlying liquid−liquid phase separation of the FUS low-complexity domain</title><title>Nature structural & molecular biology</title><addtitle>Nat Struct Mol Biol</addtitle><addtitle>Nat Struct Mol Biol</addtitle><description>The low-complexity domain of the RNA-binding protein FUS (FUS LC) mediates liquid−liquid phase separation (LLPS), but the interactions between the repetitive SYGQ-rich sequence of FUS LC that stabilize the liquid phase are not known in detail. By combining NMR and Raman spectroscopy, mutagenesis, and molecular simulation, we demonstrate that heterogeneous interactions involving all residue types underlie LLPS of human FUS LC. We find no evidence that FUS LC adopts conformations with traditional secondary structure elements in the condensed phase; rather, it maintains conformational heterogeneity. We show that hydrogen bonding, π/sp
2
, and hydrophobic interactions all contribute to stabilizing LLPS of FUS LC. In addition to contributions from tyrosine residues, we find that glutamine residues also participate in contacts leading to LLPS of FUS LC. These results support a model in which FUS LC forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.
The low-complexity domain of the RNA-binding protein FUS forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.</description><subject>631/45/535/878</subject><subject>631/45/535/878/1263</subject><subject>631/57/2269</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Biochemistry</subject><subject>Biological Microscopy</subject><subject>Biomedical and Life Sciences</subject><subject>Chemical properties</subject><subject>Compartmental analysis (Biology)</subject><subject>Complexity</subject><subject>Composition</subject><subject>Computer simulation</subject><subject>Engineering</subject><subject>FUS protein</subject><subject>Glutamine</subject><subject>Health aspects</subject><subject>Heterogeneity</subject><subject>Humans</subject><subject>Hydrogen Bonding</subject><subject>Hydrophobic and Hydrophilic Interactions</subject><subject>Hydrophobicity</subject><subject>Intrinsically disordered proteins</subject><subject>Intrinsically Disordered Proteins - chemistry</subject><subject>Life Sciences</subject><subject>Liquid phases</subject><subject>Macromolecules</subject><subject>Membrane Biology</subject><subject>Models, Molecular</subject><subject>Molecular biology</subject><subject>Molecular interactions</subject><subject>Mutagenesis</subject><subject>NMR</subject><subject>NMR spectroscopy</subject><subject>Nuclear magnetic resonance</subject><subject>Phase separation</subject><subject>Phase transformations (Statistical physics)</subject><subject>Phase Transition</subject><subject>Polypeptides</subject><subject>Protein Conformation</subject><subject>Protein Domains</subject><subject>Protein research</subject><subject>Protein Structure</subject><subject>Protein Structure, Secondary</subject><subject>Proteins</subject><subject>Raman spectroscopy</subject><subject>Residues</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA polymerase</subject><subject>RNA-binding protein</subject><subject>RNA-Binding Protein FUS - chemistry</subject><subject>Secondary structure</subject><subject>solution-state NMR</subject><subject>Spectrum analysis</subject><subject>Transcription factors</subject><subject>Tyrosine</subject><issn>1545-9993</issn><issn>1545-9985</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1ks1u1DAQxyMEoh_wAFxQBKceUmwnTuILUlVRqFSEROnZciaTrKvETm2n7L4BZx6RJ8GrlC0rgSzZY89vZjTjf5K8ouSUkrx-5wvKRZERKjLCOMnWT5JDygueCVHzpztb5AfJkfe3JEK8yp8nBzllFSkqdpjAZzsgzINyqTYBnYKgrfHpbFp0w0abPh303azbXz9-LkY6rZTH1OOknNrCqe3SsML04uY6Hez3DOw4DbjWYZO2dlTavEiedWrw-PLhPE5uLj58O_-UXX35eHl-dpVBWRYh4xRZzUgjBBDaMMGpIAhtCyCgUnlTI81Vi0TEDbsGK0VEE2-AjDctkPw4eb_kneZmxBbQBKcGOTk9KreRVmm57zF6JXt7L8uS5jXZJnizJLA-aOlBB4QVWGMQgqS8qjgXEXr7UMXZuxl9kLd2diY2JhnjtCJ1WfJHqlcDSm06GyvCqD3IMy5Y_DeW00id_oOKq8VRx8LY6fi-F3CyFxCZgOvQq9l7eXn9dZ-lCwvOeu-w202CErnVj1z0I6N-5FY_ch1jXv89wl3EH8FEgC2Ajy7To3vs_v9ZfwMGGdMH</recordid><startdate>20190701</startdate><enddate>20190701</enddate><creator>Murthy, Anastasia C.</creator><creator>Dignon, Gregory L.</creator><creator>Kan, Yelena</creator><creator>Zerze, Gül H.</creator><creator>Parekh, Sapun H.</creator><creator>Mittal, Jeetain</creator><creator>Fawzi, Nicolas L.</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>OIOZB</scope><scope>OTOTI</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8522-1854</orcidid><orcidid>https://orcid.org/0000-0002-2490-697X</orcidid><orcidid>https://orcid.org/0000-0002-9725-6402</orcidid><orcidid>https://orcid.org/0000-0001-8016-8652</orcidid><orcidid>https://orcid.org/0000-0001-5483-0577</orcidid><orcidid>https://orcid.org/0000000297256402</orcidid><orcidid>https://orcid.org/0000000185221854</orcidid><orcidid>https://orcid.org/0000000180168652</orcidid><orcidid>https://orcid.org/000000022490697X</orcidid><orcidid>https://orcid.org/0000000154830577</orcidid></search><sort><creationdate>20190701</creationdate><title>Molecular interactions underlying liquid−liquid phase separation of the FUS low-complexity domain</title><author>Murthy, Anastasia C. ; Dignon, Gregory L. ; Kan, Yelena ; Zerze, Gül H. ; Parekh, Sapun H. ; Mittal, Jeetain ; Fawzi, Nicolas L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c664t-51e2820b99c01b295190ecddcc9c7a3b8e13ade09adeefbe7a09b09ace25bdc03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>631/45/535/878</topic><topic>631/45/535/878/1263</topic><topic>631/57/2269</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>Biochemistry</topic><topic>Biological Microscopy</topic><topic>Biomedical and Life Sciences</topic><topic>Chemical properties</topic><topic>Compartmental analysis (Biology)</topic><topic>Complexity</topic><topic>Composition</topic><topic>Computer simulation</topic><topic>Engineering</topic><topic>FUS protein</topic><topic>Glutamine</topic><topic>Health aspects</topic><topic>Heterogeneity</topic><topic>Humans</topic><topic>Hydrogen Bonding</topic><topic>Hydrophobic and Hydrophilic Interactions</topic><topic>Hydrophobicity</topic><topic>Intrinsically disordered proteins</topic><topic>Intrinsically Disordered Proteins - chemistry</topic><topic>Life Sciences</topic><topic>Liquid phases</topic><topic>Macromolecules</topic><topic>Membrane Biology</topic><topic>Models, Molecular</topic><topic>Molecular biology</topic><topic>Molecular interactions</topic><topic>Mutagenesis</topic><topic>NMR</topic><topic>NMR spectroscopy</topic><topic>Nuclear magnetic resonance</topic><topic>Phase separation</topic><topic>Phase transformations (Statistical physics)</topic><topic>Phase Transition</topic><topic>Polypeptides</topic><topic>Protein Conformation</topic><topic>Protein Domains</topic><topic>Protein research</topic><topic>Protein Structure</topic><topic>Protein Structure, Secondary</topic><topic>Proteins</topic><topic>Raman spectroscopy</topic><topic>Residues</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA polymerase</topic><topic>RNA-binding protein</topic><topic>RNA-Binding Protein FUS - chemistry</topic><topic>Secondary structure</topic><topic>solution-state NMR</topic><topic>Spectrum analysis</topic><topic>Transcription factors</topic><topic>Tyrosine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Murthy, Anastasia C.</creatorcontrib><creatorcontrib>Dignon, Gregory L.</creatorcontrib><creatorcontrib>Kan, Yelena</creatorcontrib><creatorcontrib>Zerze, Gül H.</creatorcontrib><creatorcontrib>Parekh, Sapun H.</creatorcontrib><creatorcontrib>Mittal, Jeetain</creatorcontrib><creatorcontrib>Fawzi, Nicolas L.</creatorcontrib><creatorcontrib>Lehigh Univ., Bethlehem, PA (United States)</creatorcontrib><creatorcontrib>Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). 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National Energy Research Scientific Computing Center (NERSC)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular interactions underlying liquid−liquid phase separation of the FUS low-complexity domain</atitle><jtitle>Nature structural & molecular biology</jtitle><stitle>Nat Struct Mol Biol</stitle><addtitle>Nat Struct Mol Biol</addtitle><date>2019-07-01</date><risdate>2019</risdate><volume>26</volume><issue>7</issue><spage>637</spage><epage>648</epage><pages>637-648</pages><issn>1545-9993</issn><eissn>1545-9985</eissn><abstract>The low-complexity domain of the RNA-binding protein FUS (FUS LC) mediates liquid−liquid phase separation (LLPS), but the interactions between the repetitive SYGQ-rich sequence of FUS LC that stabilize the liquid phase are not known in detail. By combining NMR and Raman spectroscopy, mutagenesis, and molecular simulation, we demonstrate that heterogeneous interactions involving all residue types underlie LLPS of human FUS LC. We find no evidence that FUS LC adopts conformations with traditional secondary structure elements in the condensed phase; rather, it maintains conformational heterogeneity. We show that hydrogen bonding, π/sp
2
, and hydrophobic interactions all contribute to stabilizing LLPS of FUS LC. In addition to contributions from tyrosine residues, we find that glutamine residues also participate in contacts leading to LLPS of FUS LC. These results support a model in which FUS LC forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.
The low-complexity domain of the RNA-binding protein FUS forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>31270472</pmid><doi>10.1038/s41594-019-0250-x</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-8522-1854</orcidid><orcidid>https://orcid.org/0000-0002-2490-697X</orcidid><orcidid>https://orcid.org/0000-0002-9725-6402</orcidid><orcidid>https://orcid.org/0000-0001-8016-8652</orcidid><orcidid>https://orcid.org/0000-0001-5483-0577</orcidid><orcidid>https://orcid.org/0000000297256402</orcidid><orcidid>https://orcid.org/0000000185221854</orcidid><orcidid>https://orcid.org/0000000180168652</orcidid><orcidid>https://orcid.org/000000022490697X</orcidid><orcidid>https://orcid.org/0000000154830577</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Nature structural & molecular biology, 2019-07, Vol.26 (7), p.637-648 |
| issn | 1545-9993 1545-9985 |
| language | eng |
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| source | MEDLINE; SpringerLink Journals; Nature Journals Online |
| subjects | 631/45/535/878 631/45/535/878/1263 631/57/2269 BASIC BIOLOGICAL SCIENCES Biochemistry Biological Microscopy Biomedical and Life Sciences Chemical properties Compartmental analysis (Biology) Complexity Composition Computer simulation Engineering FUS protein Glutamine Health aspects Heterogeneity Humans Hydrogen Bonding Hydrophobic and Hydrophilic Interactions Hydrophobicity Intrinsically disordered proteins Intrinsically Disordered Proteins - chemistry Life Sciences Liquid phases Macromolecules Membrane Biology Models, Molecular Molecular biology Molecular interactions Mutagenesis NMR NMR spectroscopy Nuclear magnetic resonance Phase separation Phase transformations (Statistical physics) Phase Transition Polypeptides Protein Conformation Protein Domains Protein research Protein Structure Protein Structure, Secondary Proteins Raman spectroscopy Residues Ribonucleic acid RNA RNA polymerase RNA-binding protein RNA-Binding Protein FUS - chemistry Secondary structure solution-state NMR Spectrum analysis Transcription factors Tyrosine |
| title | Molecular interactions underlying liquid−liquid phase separation of the FUS low-complexity domain |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T04%3A08%3A57IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Molecular%20interactions%20underlying%20liquid%E2%88%92liquid%20phase%20separation%20of%20the%20FUS%20low-complexity%20domain&rft.jtitle=Nature%20structural%20&%20molecular%20biology&rft.au=Murthy,%20Anastasia%20C.&rft.aucorp=Lehigh%20Univ.,%20Bethlehem,%20PA%20(United%20States)&rft.date=2019-07-01&rft.volume=26&rft.issue=7&rft.spage=637&rft.epage=648&rft.pages=637-648&rft.issn=1545-9993&rft.eissn=1545-9985&rft_id=info:doi/10.1038/s41594-019-0250-x&rft_dat=%3Cgale_pubme%3EA592159231%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2251708665&rft_id=info:pmid/31270472&rft_galeid=A592159231&rfr_iscdi=true |