Solution structure of GAP SH3 domain by 1H NMR and spatial arrangement of essential Ras signaling‐involved sequence
Src homology 3 (SH3) domains are found in numerous cytoplasmic proteins involved in intracellular signal transduction. We used 2‐D 1H NMR to determine the structure of the SH3 domain of the guanosine triphosphatase‐activating protein (GAP), an essential component of the Ras signaling pathway. The st...
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| Veröffentlicht in: | The EMBO journal 1994-03, Vol.13 (6), p.1270-1279 |
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| creator | Yang, Y.S. Garbay, C. Duchesne, M. Cornille, F. Jullian, N. Fromage, N. Tocque, B. Roques, B.P. |
| description | Src homology 3 (SH3) domains are found in numerous cytoplasmic proteins involved in intracellular signal transduction. We used 2‐D 1H NMR to determine the structure of the SH3 domain of the guanosine triphosphatase‐activating protein (GAP), an essential component of the Ras signaling pathway. The structure of the GAP SH3 domain (275‐350) was found to be a compact beta‐barrel made of six antiparallel beta‐strands arranged in two roughly perpendicular beta‐sheets with the acidic residues located at the surface of the protein. The Trp317, Trp319, Thr321 and Leu323 residues belonging to the sequence (317‐326), which was shown to be essential for Ras signaling, formed two nearby lipophilic bulges followed by a hydrophilic domain (Arg324‐Asp326). These structural data could be used to characterize the still unidentified downstream components of GAP, which are involved in Ras signaling, and to rationally design inhibitors of this pathway. |
| doi_str_mv | 10.1002/j.1460-2075.1994.tb06379.x |
| format | Article |
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We used 2‐D 1H NMR to determine the structure of the SH3 domain of the guanosine triphosphatase‐activating protein (GAP), an essential component of the Ras signaling pathway. The structure of the GAP SH3 domain (275‐350) was found to be a compact beta‐barrel made of six antiparallel beta‐strands arranged in two roughly perpendicular beta‐sheets with the acidic residues located at the surface of the protein. The Trp317, Trp319, Thr321 and Leu323 residues belonging to the sequence (317‐326), which was shown to be essential for Ras signaling, formed two nearby lipophilic bulges followed by a hydrophilic domain (Arg324‐Asp326). These structural data could be used to characterize the still unidentified downstream components of GAP, which are involved in Ras signaling, and to rationally design inhibitors of this pathway.</description><identifier>ISSN: 0261-4189</identifier><identifier>EISSN: 1460-2075</identifier><identifier>DOI: 10.1002/j.1460-2075.1994.tb06379.x</identifier><identifier>PMID: 8137811</identifier><identifier>CODEN: EMJODG</identifier><language>eng</language><publisher>London: Nature Publishing Group</publisher><subject>Amino Acid Sequence ; Binding Sites ; Biological and medical sciences ; Computer Graphics ; Fundamental and applied biological sciences. Psychology ; GTPase-Activating Proteins ; Ligands ; Magnetic Resonance Spectroscopy ; Molecular biophysics ; Molecular Sequence Data ; Oncogene Protein p21(ras) - metabolism ; Protein Structure, Tertiary ; Proteins - chemistry ; Proteins - metabolism ; Protons ; ras GTPase-Activating Proteins ; Sequence Homology, Amino Acid ; Signal Transduction ; Structure in molecular biology ; Tridimensional structure</subject><ispartof>The EMBO journal, 1994-03, Vol.13 (6), p.1270-1279</ispartof><rights>1994 European Molecular Biology Organization</rights><rights>1994 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3549-aac986bdd875121a1414c6568459ad4e13821846d99cd62661c2ab662a87bd113</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC394941/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC394941/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3970172$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8137811$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Y.S.</creatorcontrib><creatorcontrib>Garbay, C.</creatorcontrib><creatorcontrib>Duchesne, M.</creatorcontrib><creatorcontrib>Cornille, F.</creatorcontrib><creatorcontrib>Jullian, N.</creatorcontrib><creatorcontrib>Fromage, N.</creatorcontrib><creatorcontrib>Tocque, B.</creatorcontrib><creatorcontrib>Roques, B.P.</creatorcontrib><title>Solution structure of GAP SH3 domain by 1H NMR and spatial arrangement of essential Ras signaling‐involved sequence</title><title>The EMBO journal</title><addtitle>EMBO J</addtitle><description>Src homology 3 (SH3) domains are found in numerous cytoplasmic proteins involved in intracellular signal transduction. We used 2‐D 1H NMR to determine the structure of the SH3 domain of the guanosine triphosphatase‐activating protein (GAP), an essential component of the Ras signaling pathway. The structure of the GAP SH3 domain (275‐350) was found to be a compact beta‐barrel made of six antiparallel beta‐strands arranged in two roughly perpendicular beta‐sheets with the acidic residues located at the surface of the protein. The Trp317, Trp319, Thr321 and Leu323 residues belonging to the sequence (317‐326), which was shown to be essential for Ras signaling, formed two nearby lipophilic bulges followed by a hydrophilic domain (Arg324‐Asp326). These structural data could be used to characterize the still unidentified downstream components of GAP, which are involved in Ras signaling, and to rationally design inhibitors of this pathway.</description><subject>Amino Acid Sequence</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Computer Graphics</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>GTPase-Activating Proteins</subject><subject>Ligands</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Molecular biophysics</subject><subject>Molecular Sequence Data</subject><subject>Oncogene Protein p21(ras) - metabolism</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins - chemistry</subject><subject>Proteins - metabolism</subject><subject>Protons</subject><subject>ras GTPase-Activating Proteins</subject><subject>Sequence Homology, Amino Acid</subject><subject>Signal Transduction</subject><subject>Structure in molecular biology</subject><subject>Tridimensional structure</subject><issn>0261-4189</issn><issn>1460-2075</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqVkdFu0zAUhi0EGmXwCEgWQtwl-CSOYyNxUaaxgjZAG1xbJ45bXKV2iZOy3u0R9ow8CQmNKrjkykf6_-_41_kJeQEsBcay1-sUuGBJxsoiBaV42lVM5KVKbx-Q2VF6SGYsE5BwkOoxeRLjmjFWyBJOyImEvJQAM9LfhKbvXPA0dm1vur61NCzpxfwLvVnktA4bdJ5WewoL-unqmqKvadxi57Ch2LboV3ZjfTcyNsZhGoVrjDS6lcfG-dWvu3vnd6HZ2YG0P3rrjX1KHi2xifbZ9J6Sb-_Pv54tksvPFx_O5peJyQuuEkSjpKjqWpYFZIDAgRtRCMkLhTW3kMsMJBe1UqYWmRBgMqyEyFCWVQ2Qn5K3h73bvtrY2gz5Wmz0tnUbbPc6oNP_Kt5916uw07niio_8q4lvw5A8dnrjorFNg96GPupS5EoBzwbjm4PRtCHG1i6PfwDTY2d6rcdi9FiMHjvTU2f6doCf_53yiE4lDfrLScdosFkOVzcuHm25KhmUY4b5wfbTNXb_HwH0-dW7j3_m_Dcoq7Z1</recordid><startdate>19940315</startdate><enddate>19940315</enddate><creator>Yang, Y.S.</creator><creator>Garbay, C.</creator><creator>Duchesne, M.</creator><creator>Cornille, F.</creator><creator>Jullian, N.</creator><creator>Fromage, N.</creator><creator>Tocque, B.</creator><creator>Roques, B.P.</creator><general>Nature Publishing Group</general><scope>IQODW</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>19940315</creationdate><title>Solution structure of GAP SH3 domain by 1H NMR and spatial arrangement of essential Ras signaling‐involved sequence</title><author>Yang, Y.S. ; Garbay, C. ; Duchesne, M. ; Cornille, F. ; Jullian, N. ; Fromage, N. ; Tocque, B. ; Roques, B.P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3549-aac986bdd875121a1414c6568459ad4e13821846d99cd62661c2ab662a87bd113</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>Amino Acid Sequence</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Computer Graphics</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>GTPase-Activating Proteins</topic><topic>Ligands</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Molecular biophysics</topic><topic>Molecular Sequence Data</topic><topic>Oncogene Protein p21(ras) - metabolism</topic><topic>Protein Structure, Tertiary</topic><topic>Proteins - chemistry</topic><topic>Proteins - metabolism</topic><topic>Protons</topic><topic>ras GTPase-Activating Proteins</topic><topic>Sequence Homology, Amino Acid</topic><topic>Signal Transduction</topic><topic>Structure in molecular biology</topic><topic>Tridimensional structure</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Y.S.</creatorcontrib><creatorcontrib>Garbay, C.</creatorcontrib><creatorcontrib>Duchesne, M.</creatorcontrib><creatorcontrib>Cornille, F.</creatorcontrib><creatorcontrib>Jullian, N.</creatorcontrib><creatorcontrib>Fromage, N.</creatorcontrib><creatorcontrib>Tocque, B.</creatorcontrib><creatorcontrib>Roques, B.P.</creatorcontrib><collection>Pascal-Francis</collection><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>PubMed Central (Full Participant titles)</collection><jtitle>The EMBO journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Y.S.</au><au>Garbay, C.</au><au>Duchesne, M.</au><au>Cornille, F.</au><au>Jullian, N.</au><au>Fromage, N.</au><au>Tocque, B.</au><au>Roques, B.P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Solution structure of GAP SH3 domain by 1H NMR and spatial arrangement of essential Ras signaling‐involved sequence</atitle><jtitle>The EMBO journal</jtitle><addtitle>EMBO J</addtitle><date>1994-03-15</date><risdate>1994</risdate><volume>13</volume><issue>6</issue><spage>1270</spage><epage>1279</epage><pages>1270-1279</pages><issn>0261-4189</issn><eissn>1460-2075</eissn><coden>EMJODG</coden><abstract>Src homology 3 (SH3) domains are found in numerous cytoplasmic proteins involved in intracellular signal transduction. We used 2‐D 1H NMR to determine the structure of the SH3 domain of the guanosine triphosphatase‐activating protein (GAP), an essential component of the Ras signaling pathway. The structure of the GAP SH3 domain (275‐350) was found to be a compact beta‐barrel made of six antiparallel beta‐strands arranged in two roughly perpendicular beta‐sheets with the acidic residues located at the surface of the protein. The Trp317, Trp319, Thr321 and Leu323 residues belonging to the sequence (317‐326), which was shown to be essential for Ras signaling, formed two nearby lipophilic bulges followed by a hydrophilic domain (Arg324‐Asp326). 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| subjects | Amino Acid Sequence Binding Sites Biological and medical sciences Computer Graphics Fundamental and applied biological sciences. Psychology GTPase-Activating Proteins Ligands Magnetic Resonance Spectroscopy Molecular biophysics Molecular Sequence Data Oncogene Protein p21(ras) - metabolism Protein Structure, Tertiary Proteins - chemistry Proteins - metabolism Protons ras GTPase-Activating Proteins Sequence Homology, Amino Acid Signal Transduction Structure in molecular biology Tridimensional structure |
| title | Solution structure of GAP SH3 domain by 1H NMR and spatial arrangement of essential Ras signaling‐involved sequence |
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