Structural basis for R-spondin recognition by LGR4/5/6 receptors
The R-spondin (RSPO) family of secreted proteins (RSPO1-RSPO4) has pleiotropic functions in development and stem cell growth by strongly enhancing Wnt pathway activation. Recently, leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), LGR5, and LGR6 have been identified as receptors fo...
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| Veröffentlicht in: | Genes & development 2013-06, Vol.27 (12), p.1339-1344 |
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| creator | Wang, Dongli Huang, Binlu Zhang, Senyan Yu, Xiaojuan Wu, Wei Wang, Xinquan |
| description | The R-spondin (RSPO) family of secreted proteins (RSPO1-RSPO4) has pleiotropic functions in development and stem cell growth by strongly enhancing Wnt pathway activation. Recently, leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), LGR5, and LGR6 have been identified as receptors for RSPOs. Here we report the complex structure of the LGR4 extracellular domain (ECD) with the RSPO1 N-terminal fragment (RSPO1-2F) containing two adjacent furin-like cysteine-rich domains (FU-CRDs). The LGR4-ECD adopts the anticipated TLR horseshoe structure and uses its concave surface close to the N termini to bind RSPO1-2F. Both the FU-CRD1 and FU-CRD2 domains of RSPO1 contribute to LGR4 interaction, and binding and cellular assays identified critical RSPO1 residues for its biological activities. Our results define the molecular mechanism by which the LGR4/5/6 receptors recognize RSPOs and also provide structural insights into the signaling difference between the LGR4/5/6 receptors and other members in the LGR family. |
| doi_str_mv | 10.1101/gad.219360.113 |
| format | Article |
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Recently, leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), LGR5, and LGR6 have been identified as receptors for RSPOs. Here we report the complex structure of the LGR4 extracellular domain (ECD) with the RSPO1 N-terminal fragment (RSPO1-2F) containing two adjacent furin-like cysteine-rich domains (FU-CRDs). The LGR4-ECD adopts the anticipated TLR horseshoe structure and uses its concave surface close to the N termini to bind RSPO1-2F. Both the FU-CRD1 and FU-CRD2 domains of RSPO1 contribute to LGR4 interaction, and binding and cellular assays identified critical RSPO1 residues for its biological activities. Our results define the molecular mechanism by which the LGR4/5/6 receptors recognize RSPOs and also provide structural insights into the signaling difference between the LGR4/5/6 receptors and other members in the LGR family.</description><identifier>ISSN: 0890-9369</identifier><identifier>EISSN: 1549-5477</identifier><identifier>DOI: 10.1101/gad.219360.113</identifier><identifier>PMID: 23756652</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>Amino Acid Sequence ; Animals ; Cell Line ; Humans ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Protein Binding ; Protein Structure, Tertiary ; Receptors, G-Protein-Coupled - chemistry ; Receptors, G-Protein-Coupled - genetics ; Receptors, G-Protein-Coupled - metabolism ; Research Communication ; Sequence Alignment ; Signal Transduction ; Thrombospondins - chemistry ; Thrombospondins - genetics ; Thrombospondins - metabolism</subject><ispartof>Genes & development, 2013-06, Vol.27 (12), p.1339-1344</ispartof><rights>Copyright © 2013 by Cold Spring Harbor Laboratory Press 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c489t-9fec4c8ddf5a7730430338a239f571f40b210262feac773d797bcb98ea4191a43</citedby><cites>FETCH-LOGICAL-c489t-9fec4c8ddf5a7730430338a239f571f40b210262feac773d797bcb98ea4191a43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701189/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701189/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23756652$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Dongli</creatorcontrib><creatorcontrib>Huang, Binlu</creatorcontrib><creatorcontrib>Zhang, Senyan</creatorcontrib><creatorcontrib>Yu, Xiaojuan</creatorcontrib><creatorcontrib>Wu, Wei</creatorcontrib><creatorcontrib>Wang, Xinquan</creatorcontrib><title>Structural basis for R-spondin recognition by LGR4/5/6 receptors</title><title>Genes & development</title><addtitle>Genes Dev</addtitle><description>The R-spondin (RSPO) family of secreted proteins (RSPO1-RSPO4) has pleiotropic functions in development and stem cell growth by strongly enhancing Wnt pathway activation. Recently, leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), LGR5, and LGR6 have been identified as receptors for RSPOs. Here we report the complex structure of the LGR4 extracellular domain (ECD) with the RSPO1 N-terminal fragment (RSPO1-2F) containing two adjacent furin-like cysteine-rich domains (FU-CRDs). The LGR4-ECD adopts the anticipated TLR horseshoe structure and uses its concave surface close to the N termini to bind RSPO1-2F. Both the FU-CRD1 and FU-CRD2 domains of RSPO1 contribute to LGR4 interaction, and binding and cellular assays identified critical RSPO1 residues for its biological activities. Our results define the molecular mechanism by which the LGR4/5/6 receptors recognize RSPOs and also provide structural insights into the signaling difference between the LGR4/5/6 receptors and other members in the LGR family.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Cell Line</subject><subject>Humans</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Protein Binding</subject><subject>Protein Structure, Tertiary</subject><subject>Receptors, G-Protein-Coupled - chemistry</subject><subject>Receptors, G-Protein-Coupled - genetics</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Research Communication</subject><subject>Sequence Alignment</subject><subject>Signal Transduction</subject><subject>Thrombospondins - chemistry</subject><subject>Thrombospondins - genetics</subject><subject>Thrombospondins - metabolism</subject><issn>0890-9369</issn><issn>1549-5477</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUU1LAzEQDaJorV49yh69bJuvTTYXUYpWoSBUPYdsNqmR7aYmu0L_vamtRU9eZph5bx4z8wC4QHCEEETjhapHGAnCNjU5AANUUJEXlPNDMIClgHnCxAk4jfEdQsggY8fgBBNeMFbgAbh57kKvuz6oJqtUdDGzPmTzPK58W7s2C0b7Res659usWmez6ZyOizHb9M2q8yGegSOrmmjOd3kIXu_vXiYP-exp-ji5neWalqLLhTWa6rKubaE4J5ASSEipMBG24MhSWGEEMcPWKJ3wmgte6UqURlEkkKJkCK63uqu-Wppam7ZLO8tVcEsV1tIrJ_8irXuTC_8pCYcIlSIJXO0Egv_oTezk0kVtmka1xvdRIvr9RoTw_9SkydILUxiC0Zaqg48xGLvfCEG5cUgmh-TWoVSTNHD5-449_ccS8gUG_Ytr</recordid><startdate>20130615</startdate><enddate>20130615</enddate><creator>Wang, Dongli</creator><creator>Huang, Binlu</creator><creator>Zhang, Senyan</creator><creator>Yu, Xiaojuan</creator><creator>Wu, Wei</creator><creator>Wang, Xinquan</creator><general>Cold Spring Harbor Laboratory Press</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>7X8</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20130615</creationdate><title>Structural basis for R-spondin recognition by LGR4/5/6 receptors</title><author>Wang, Dongli ; Huang, Binlu ; Zhang, Senyan ; Yu, Xiaojuan ; Wu, Wei ; Wang, Xinquan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c489t-9fec4c8ddf5a7730430338a239f571f40b210262feac773d797bcb98ea4191a43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Cell Line</topic><topic>Humans</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Protein Binding</topic><topic>Protein Structure, Tertiary</topic><topic>Receptors, G-Protein-Coupled - chemistry</topic><topic>Receptors, G-Protein-Coupled - genetics</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Research Communication</topic><topic>Sequence Alignment</topic><topic>Signal Transduction</topic><topic>Thrombospondins - chemistry</topic><topic>Thrombospondins - genetics</topic><topic>Thrombospondins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Dongli</creatorcontrib><creatorcontrib>Huang, Binlu</creatorcontrib><creatorcontrib>Zhang, Senyan</creatorcontrib><creatorcontrib>Yu, Xiaojuan</creatorcontrib><creatorcontrib>Wu, Wei</creatorcontrib><creatorcontrib>Wang, Xinquan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genes & development</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Dongli</au><au>Huang, Binlu</au><au>Zhang, Senyan</au><au>Yu, Xiaojuan</au><au>Wu, Wei</au><au>Wang, Xinquan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural basis for R-spondin recognition by LGR4/5/6 receptors</atitle><jtitle>Genes & development</jtitle><addtitle>Genes Dev</addtitle><date>2013-06-15</date><risdate>2013</risdate><volume>27</volume><issue>12</issue><spage>1339</spage><epage>1344</epage><pages>1339-1344</pages><issn>0890-9369</issn><eissn>1549-5477</eissn><abstract>The R-spondin (RSPO) family of secreted proteins (RSPO1-RSPO4) has pleiotropic functions in development and stem cell growth by strongly enhancing Wnt pathway activation. Recently, leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), LGR5, and LGR6 have been identified as receptors for RSPOs. Here we report the complex structure of the LGR4 extracellular domain (ECD) with the RSPO1 N-terminal fragment (RSPO1-2F) containing two adjacent furin-like cysteine-rich domains (FU-CRDs). The LGR4-ECD adopts the anticipated TLR horseshoe structure and uses its concave surface close to the N termini to bind RSPO1-2F. Both the FU-CRD1 and FU-CRD2 domains of RSPO1 contribute to LGR4 interaction, and binding and cellular assays identified critical RSPO1 residues for its biological activities. Our results define the molecular mechanism by which the LGR4/5/6 receptors recognize RSPOs and also provide structural insights into the signaling difference between the LGR4/5/6 receptors and other members in the LGR family.</abstract><cop>United States</cop><pub>Cold Spring Harbor Laboratory Press</pub><pmid>23756652</pmid><doi>10.1101/gad.219360.113</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Amino Acid Sequence Animals Cell Line Humans Models, Molecular Molecular Sequence Data Mutation Protein Binding Protein Structure, Tertiary Receptors, G-Protein-Coupled - chemistry Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Research Communication Sequence Alignment Signal Transduction Thrombospondins - chemistry Thrombospondins - genetics Thrombospondins - metabolism |
| title | Structural basis for R-spondin recognition by LGR4/5/6 receptors |
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