Structural mechanism underpinning Thermus oshimai Pif1‐mediated G‐quadruplex unfolding
G‐quadruplexes (G4s) are unusual stable DNA structures that cause genomic instability. To overcome the potential barriers formed by G4s, cells have evolved different families of proteins that unfold G4s. Pif1 is a DNA helicase from superfamily 1 (SF1) conserved from bacteria to humans with high G4‐u...
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| creator | Dai, Yang‐Xue Guo, Hai‐Lei Liu, Na‐Nv Chen, Wei‐Fei Ai, Xia Li, Hai‐Hong Sun, Bo Hou, Xi‐Miao Rety, Stephane Xi, Xu‐Guang |
| description | G‐quadruplexes (G4s) are unusual stable DNA structures that cause genomic instability. To overcome the potential barriers formed by G4s, cells have evolved different families of proteins that unfold G4s. Pif1 is a DNA helicase from superfamily 1 (SF1) conserved from bacteria to humans with high G4‐unwinding activity. Here, we present the first X‐ray crystal structure of the
Thermus oshimai
Pif1 (
To
Pif1) complexed with a G4. Our structure reveals that
To
Pif1 recognizes the entire native G4 via a cluster of amino acids at domains 1B/2B which constitute a G4‐Recognizing Surface (GRS). The overall structure of the G4 maintains its three‐layered propeller‐type G4 topology, without significant reorganization of G‐tetrads upon protein binding. The three G‐tetrads in G4 are recognized by GRS residues mainly through electrostatic, ionic interactions, and hydrogen bonds formed between the GRS residues and the ribose‐phosphate backbone. Compared with previously solved structures of SF2 helicases in complex with G4, our structure reveals how helicases from distinct superfamilies adopt different strategies for recognizing and unfolding G4s.
Synopsis
The X‐ray crystal structure of the ToPif1 helicase complexed with a G‐quadruplex DNA (G4) mimicking the physiological G4 formed during DNA replication reveals molecular aspects of helicase‐mediated G‐quadruplex unfolding.
ToPif1 unfolds G4 in an ATP‐dependent manner without topological preference.
ToPif1 binds the integral G4 structure without a G4‐specific targeting motif.
ToPif1 recognizes the entire native G4 via a G4‐Recognizing Surface (GRS) which exhibits different interactions with different tetrads showing that helicases from distinct superfamilies adopt different strategies for recognizing and unfolding G4s.
Graphical Abstract
The crystal structure of ToPif1 complexed with a G4 shows that ToPif1 recognizes the entire native G4 via a G4‐Recognizing Surface. It reveals how helicases from distinct superfamilies use different strategies for recognizing and unfolding G4s. |
| doi_str_mv | 10.15252/embr.202153874 |
| format | Article |
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Thermus oshimai
Pif1 (
To
Pif1) complexed with a G4. Our structure reveals that
To
Pif1 recognizes the entire native G4 via a cluster of amino acids at domains 1B/2B which constitute a G4‐Recognizing Surface (GRS). The overall structure of the G4 maintains its three‐layered propeller‐type G4 topology, without significant reorganization of G‐tetrads upon protein binding. The three G‐tetrads in G4 are recognized by GRS residues mainly through electrostatic, ionic interactions, and hydrogen bonds formed between the GRS residues and the ribose‐phosphate backbone. Compared with previously solved structures of SF2 helicases in complex with G4, our structure reveals how helicases from distinct superfamilies adopt different strategies for recognizing and unfolding G4s.
Synopsis
The X‐ray crystal structure of the ToPif1 helicase complexed with a G‐quadruplex DNA (G4) mimicking the physiological G4 formed during DNA replication reveals molecular aspects of helicase‐mediated G‐quadruplex unfolding.
ToPif1 unfolds G4 in an ATP‐dependent manner without topological preference.
ToPif1 binds the integral G4 structure without a G4‐specific targeting motif.
ToPif1 recognizes the entire native G4 via a G4‐Recognizing Surface (GRS) which exhibits different interactions with different tetrads showing that helicases from distinct superfamilies adopt different strategies for recognizing and unfolding G4s.
Graphical Abstract
The crystal structure of ToPif1 complexed with a G4 shows that ToPif1 recognizes the entire native G4 via a G4‐Recognizing Surface. It reveals how helicases from distinct superfamilies use different strategies for recognizing and unfolding G4s.</description><identifier>ISSN: 1469-221X</identifier><identifier>EISSN: 1469-3178</identifier><identifier>DOI: 10.15252/embr.202153874</identifier><identifier>PMID: 35736675</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Amino acids ; Bacteriology ; Biochemistry, Molecular Biology ; Crystal structure ; Deoxyribonucleic acid ; DNA ; DNA - metabolism ; DNA biosynthesis ; DNA helicase ; DNA Helicases - genetics ; DNA Helicases - metabolism ; Electrostatic properties ; EMBO13 ; EMBO40 ; G-Quadruplexes ; G4‐Recognizing Surface ; Genomic Instability ; Humans ; Hydrogen bonding ; Hydrogen bonds ; Ionic interactions ; Life Sciences ; Microbiology and Parasitology ; Potential barriers ; Proteins ; Residues ; Ribose ; Structural Biology ; structures ; Tetrads ; Thermus ; ToPif1 ; Topology ; Unwinding ; X‐ray</subject><ispartof>EMBO reports, 2022-07, Vol.23 (7), p.e53874-n/a</ispartof><rights>The Author(s) 2022</rights><rights>2022 The Authors</rights><rights>2022 The Authors.</rights><rights>2022 EMBO</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5474-54ddf9bcaa20dda50e50090671d254a7d438b5724f3a75fc92986c939afdb3e33</citedby><cites>FETCH-LOGICAL-c5474-54ddf9bcaa20dda50e50090671d254a7d438b5724f3a75fc92986c939afdb3e33</cites><orcidid>0000-0002-4590-7795 ; 0000-0002-2089-6727 ; 0000-0002-2117-1066 ; 0000-0002-2272-3256 ; 0000-0003-3499-443X ; 0000-0002-6335-2009 ; 0000-0002-7376-0292 ; 0000-0003-2410-1087</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9253758/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9253758/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,1417,1433,27924,27925,41120,42189,45574,45575,46409,46833,51576,53791,53793</link.rule.ids><linktorsrc>$$Uhttps://doi.org/10.15252/embr.202153874$$EView_record_in_Springer_Nature$$FView_record_in_$$GSpringer_Nature</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35736675$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-03718467$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Dai, Yang‐Xue</creatorcontrib><creatorcontrib>Guo, Hai‐Lei</creatorcontrib><creatorcontrib>Liu, Na‐Nv</creatorcontrib><creatorcontrib>Chen, Wei‐Fei</creatorcontrib><creatorcontrib>Ai, Xia</creatorcontrib><creatorcontrib>Li, Hai‐Hong</creatorcontrib><creatorcontrib>Sun, Bo</creatorcontrib><creatorcontrib>Hou, Xi‐Miao</creatorcontrib><creatorcontrib>Rety, Stephane</creatorcontrib><creatorcontrib>Xi, Xu‐Guang</creatorcontrib><title>Structural mechanism underpinning Thermus oshimai Pif1‐mediated G‐quadruplex unfolding</title><title>EMBO reports</title><addtitle>EMBO Rep</addtitle><addtitle>EMBO Rep</addtitle><description>G‐quadruplexes (G4s) are unusual stable DNA structures that cause genomic instability. To overcome the potential barriers formed by G4s, cells have evolved different families of proteins that unfold G4s. Pif1 is a DNA helicase from superfamily 1 (SF1) conserved from bacteria to humans with high G4‐unwinding activity. Here, we present the first X‐ray crystal structure of the
Thermus oshimai
Pif1 (
To
Pif1) complexed with a G4. Our structure reveals that
To
Pif1 recognizes the entire native G4 via a cluster of amino acids at domains 1B/2B which constitute a G4‐Recognizing Surface (GRS). The overall structure of the G4 maintains its three‐layered propeller‐type G4 topology, without significant reorganization of G‐tetrads upon protein binding. The three G‐tetrads in G4 are recognized by GRS residues mainly through electrostatic, ionic interactions, and hydrogen bonds formed between the GRS residues and the ribose‐phosphate backbone. Compared with previously solved structures of SF2 helicases in complex with G4, our structure reveals how helicases from distinct superfamilies adopt different strategies for recognizing and unfolding G4s.
Synopsis
The X‐ray crystal structure of the ToPif1 helicase complexed with a G‐quadruplex DNA (G4) mimicking the physiological G4 formed during DNA replication reveals molecular aspects of helicase‐mediated G‐quadruplex unfolding.
ToPif1 unfolds G4 in an ATP‐dependent manner without topological preference.
ToPif1 binds the integral G4 structure without a G4‐specific targeting motif.
ToPif1 recognizes the entire native G4 via a G4‐Recognizing Surface (GRS) which exhibits different interactions with different tetrads showing that helicases from distinct superfamilies adopt different strategies for recognizing and unfolding G4s.
Graphical Abstract
The crystal structure of ToPif1 complexed with a G4 shows that ToPif1 recognizes the entire native G4 via a G4‐Recognizing Surface. It reveals how helicases from distinct superfamilies use different strategies for recognizing and unfolding G4s.</description><subject>Amino acids</subject><subject>Bacteriology</subject><subject>Biochemistry, Molecular Biology</subject><subject>Crystal structure</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA - metabolism</subject><subject>DNA biosynthesis</subject><subject>DNA helicase</subject><subject>DNA Helicases - genetics</subject><subject>DNA Helicases - metabolism</subject><subject>Electrostatic properties</subject><subject>EMBO13</subject><subject>EMBO40</subject><subject>G-Quadruplexes</subject><subject>G4‐Recognizing Surface</subject><subject>Genomic Instability</subject><subject>Humans</subject><subject>Hydrogen bonding</subject><subject>Hydrogen bonds</subject><subject>Ionic interactions</subject><subject>Life Sciences</subject><subject>Microbiology and Parasitology</subject><subject>Potential barriers</subject><subject>Proteins</subject><subject>Residues</subject><subject>Ribose</subject><subject>Structural Biology</subject><subject>structures</subject><subject>Tetrads</subject><subject>Thermus</subject><subject>ToPif1</subject><subject>Topology</subject><subject>Unwinding</subject><subject>X‐ray</subject><issn>1469-221X</issn><issn>1469-3178</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9u1DAYxC1ERUvhzA1F4gKHbf03djhUKlVpkRaBoEiIi-XYzsZV4mztuNAbj9Bn7JPUS5alVEKc4ti_Gc_nAeAZgnuIYYb3bV-HPQwxYkRw-gDsIFpWM4K4eLheY4y-boPHMZ5DCFnFxSOwTRgnZcnZDvj2eQxJjymoruitbpV3sS-SNzYsnffOL4qz1oY-xWKIreuVKz66Bt38vO6tcWq0pjjJPxdJmZCWnf2Rtc3QmSx8ArYa1UX7dP3dBV_eHp8dnc7mH07eHR3OZ5pRTmeMGtNUtVYKQ2MUg5ZBWMGSI4MZVdxQImrGMW2I4qzRFa5EqStSqcbUxBKyCw4m32Wqcyht_ZinkcuQ04YrOSgn_z7xrpWL4VJWmBHORDZ4NRm092Snh3O52oOEI0FLfoky-3J9WRguko2j7F3UtuuUt0OKEpcC4owjnNEX99DzIQWfn2JF5akgFjxT-xOlwxBjsM0mAYLyV8dy1bHcdJwVz-_Ou-F_l5qB1xPw3XX26n9-8vj9m0933eEkjlnnFzb8Sf2vQLeVWcaM</recordid><startdate>20220705</startdate><enddate>20220705</enddate><creator>Dai, Yang‐Xue</creator><creator>Guo, Hai‐Lei</creator><creator>Liu, Na‐Nv</creator><creator>Chen, Wei‐Fei</creator><creator>Ai, Xia</creator><creator>Li, Hai‐Hong</creator><creator>Sun, Bo</creator><creator>Hou, Xi‐Miao</creator><creator>Rety, Stephane</creator><creator>Xi, Xu‐Guang</creator><general>Nature Publishing Group UK</general><general>Blackwell Publishing Ltd</general><general>EMBO Press</general><general>John Wiley and Sons Inc</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>7QL</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4590-7795</orcidid><orcidid>https://orcid.org/0000-0002-2089-6727</orcidid><orcidid>https://orcid.org/0000-0002-2117-1066</orcidid><orcidid>https://orcid.org/0000-0002-2272-3256</orcidid><orcidid>https://orcid.org/0000-0003-3499-443X</orcidid><orcidid>https://orcid.org/0000-0002-6335-2009</orcidid><orcidid>https://orcid.org/0000-0002-7376-0292</orcidid><orcidid>https://orcid.org/0000-0003-2410-1087</orcidid></search><sort><creationdate>20220705</creationdate><title>Structural mechanism underpinning Thermus oshimai Pif1‐mediated G‐quadruplex unfolding</title><author>Dai, Yang‐Xue ; Guo, Hai‐Lei ; Liu, Na‐Nv ; Chen, Wei‐Fei ; Ai, Xia ; Li, Hai‐Hong ; Sun, Bo ; Hou, Xi‐Miao ; Rety, Stephane ; Xi, Xu‐Guang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5474-54ddf9bcaa20dda50e50090671d254a7d438b5724f3a75fc92986c939afdb3e33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Amino acids</topic><topic>Bacteriology</topic><topic>Biochemistry, Molecular Biology</topic><topic>Crystal structure</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA - metabolism</topic><topic>DNA biosynthesis</topic><topic>DNA helicase</topic><topic>DNA Helicases - genetics</topic><topic>DNA Helicases - metabolism</topic><topic>Electrostatic properties</topic><topic>EMBO13</topic><topic>EMBO40</topic><topic>G-Quadruplexes</topic><topic>G4‐Recognizing Surface</topic><topic>Genomic Instability</topic><topic>Humans</topic><topic>Hydrogen bonding</topic><topic>Hydrogen bonds</topic><topic>Ionic interactions</topic><topic>Life Sciences</topic><topic>Microbiology and Parasitology</topic><topic>Potential barriers</topic><topic>Proteins</topic><topic>Residues</topic><topic>Ribose</topic><topic>Structural Biology</topic><topic>structures</topic><topic>Tetrads</topic><topic>Thermus</topic><topic>ToPif1</topic><topic>Topology</topic><topic>Unwinding</topic><topic>X‐ray</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dai, Yang‐Xue</creatorcontrib><creatorcontrib>Guo, Hai‐Lei</creatorcontrib><creatorcontrib>Liu, Na‐Nv</creatorcontrib><creatorcontrib>Chen, Wei‐Fei</creatorcontrib><creatorcontrib>Ai, Xia</creatorcontrib><creatorcontrib>Li, Hai‐Hong</creatorcontrib><creatorcontrib>Sun, Bo</creatorcontrib><creatorcontrib>Hou, Xi‐Miao</creatorcontrib><creatorcontrib>Rety, Stephane</creatorcontrib><creatorcontrib>Xi, Xu‐Guang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>EMBO reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Dai, Yang‐Xue</au><au>Guo, Hai‐Lei</au><au>Liu, Na‐Nv</au><au>Chen, Wei‐Fei</au><au>Ai, Xia</au><au>Li, Hai‐Hong</au><au>Sun, Bo</au><au>Hou, Xi‐Miao</au><au>Rety, Stephane</au><au>Xi, Xu‐Guang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural mechanism underpinning Thermus oshimai Pif1‐mediated G‐quadruplex unfolding</atitle><jtitle>EMBO reports</jtitle><stitle>EMBO Rep</stitle><addtitle>EMBO Rep</addtitle><date>2022-07-05</date><risdate>2022</risdate><volume>23</volume><issue>7</issue><spage>e53874</spage><epage>n/a</epage><pages>e53874-n/a</pages><issn>1469-221X</issn><eissn>1469-3178</eissn><abstract>G‐quadruplexes (G4s) are unusual stable DNA structures that cause genomic instability. To overcome the potential barriers formed by G4s, cells have evolved different families of proteins that unfold G4s. Pif1 is a DNA helicase from superfamily 1 (SF1) conserved from bacteria to humans with high G4‐unwinding activity. Here, we present the first X‐ray crystal structure of the
Thermus oshimai
Pif1 (
To
Pif1) complexed with a G4. Our structure reveals that
To
Pif1 recognizes the entire native G4 via a cluster of amino acids at domains 1B/2B which constitute a G4‐Recognizing Surface (GRS). The overall structure of the G4 maintains its three‐layered propeller‐type G4 topology, without significant reorganization of G‐tetrads upon protein binding. The three G‐tetrads in G4 are recognized by GRS residues mainly through electrostatic, ionic interactions, and hydrogen bonds formed between the GRS residues and the ribose‐phosphate backbone. Compared with previously solved structures of SF2 helicases in complex with G4, our structure reveals how helicases from distinct superfamilies adopt different strategies for recognizing and unfolding G4s.
Synopsis
The X‐ray crystal structure of the ToPif1 helicase complexed with a G‐quadruplex DNA (G4) mimicking the physiological G4 formed during DNA replication reveals molecular aspects of helicase‐mediated G‐quadruplex unfolding.
ToPif1 unfolds G4 in an ATP‐dependent manner without topological preference.
ToPif1 binds the integral G4 structure without a G4‐specific targeting motif.
ToPif1 recognizes the entire native G4 via a G4‐Recognizing Surface (GRS) which exhibits different interactions with different tetrads showing that helicases from distinct superfamilies adopt different strategies for recognizing and unfolding G4s.
Graphical Abstract
The crystal structure of ToPif1 complexed with a G4 shows that ToPif1 recognizes the entire native G4 via a G4‐Recognizing Surface. It reveals how helicases from distinct superfamilies use different strategies for recognizing and unfolding G4s.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>35736675</pmid><doi>10.15252/embr.202153874</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-4590-7795</orcidid><orcidid>https://orcid.org/0000-0002-2089-6727</orcidid><orcidid>https://orcid.org/0000-0002-2117-1066</orcidid><orcidid>https://orcid.org/0000-0002-2272-3256</orcidid><orcidid>https://orcid.org/0000-0003-3499-443X</orcidid><orcidid>https://orcid.org/0000-0002-6335-2009</orcidid><orcidid>https://orcid.org/0000-0002-7376-0292</orcidid><orcidid>https://orcid.org/0000-0003-2410-1087</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | EMBO reports, 2022-07, Vol.23 (7), p.e53874-n/a |
| issn | 1469-221X 1469-3178 |
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| source | Springer Nature OA Free Journals |
| subjects | Amino acids Bacteriology Biochemistry, Molecular Biology Crystal structure Deoxyribonucleic acid DNA DNA - metabolism DNA biosynthesis DNA helicase DNA Helicases - genetics DNA Helicases - metabolism Electrostatic properties EMBO13 EMBO40 G-Quadruplexes G4‐Recognizing Surface Genomic Instability Humans Hydrogen bonding Hydrogen bonds Ionic interactions Life Sciences Microbiology and Parasitology Potential barriers Proteins Residues Ribose Structural Biology structures Tetrads Thermus ToPif1 Topology Unwinding X‐ray |
| title | Structural mechanism underpinning Thermus oshimai Pif1‐mediated G‐quadruplex unfolding |
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