CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation
Mutations in the essential adaptor proteins CCM2 or CCM3 lead to cerebral cavernous malformations (CCM), vascular lesions that most frequently occur in the brain and are strongly associated with hemorrhagic stroke, seizures, and other neurological disorders. CCM2 binds CCM3, but the molecular basis...
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| Veröffentlicht in: | J. Cell Biol 2015-03, Vol.208 (7), p.987-1001 |
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| creator | Draheim, Kyle M Li, Xiaofeng Zhang, Rong Fisher, Oriana S Villari, Giulia Boggon, Titus J Calderwood, David A |
| description | Mutations in the essential adaptor proteins CCM2 or CCM3 lead to cerebral cavernous malformations (CCM), vascular lesions that most frequently occur in the brain and are strongly associated with hemorrhagic stroke, seizures, and other neurological disorders. CCM2 binds CCM3, but the molecular basis of this interaction, and its functional significance, have not been elucidated. Here, we used x-ray crystallography and structure-guided mutagenesis to show that an α-helical LD-like motif within CCM2 binds the highly conserved "HP1" pocket of the CCM3 focal adhesion targeting (FAT) homology domain. By knocking down CCM2 or CCM3 and rescuing with binding-deficient mutants, we establish that CCM2-CCM3 interactions protect CCM2 and CCM3 proteins from proteasomal degradation and show that both CCM2 and CCM3 are required for normal endothelial cell network formation. However, CCM3 expression in the absence of CCM2 is sufficient to support normal cell growth, revealing complex-independent roles for CCM3. |
| doi_str_mv | 10.1083/jcb.201407129 |
| format | Article |
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(ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>Mutations in the essential adaptor proteins CCM2 or CCM3 lead to cerebral cavernous malformations (CCM), vascular lesions that most frequently occur in the brain and are strongly associated with hemorrhagic stroke, seizures, and other neurological disorders. CCM2 binds CCM3, but the molecular basis of this interaction, and its functional significance, have not been elucidated. Here, we used x-ray crystallography and structure-guided mutagenesis to show that an α-helical LD-like motif within CCM2 binds the highly conserved "HP1" pocket of the CCM3 focal adhesion targeting (FAT) homology domain. By knocking down CCM2 or CCM3 and rescuing with binding-deficient mutants, we establish that CCM2-CCM3 interactions protect CCM2 and CCM3 proteins from proteasomal degradation and show that both CCM2 and CCM3 are required for normal endothelial cell network formation. However, CCM3 expression in the absence of CCM2 is sufficient to support normal cell growth, revealing complex-independent roles for CCM3.</description><identifier>ISSN: 0021-9525</identifier><identifier>EISSN: 1540-8140</identifier><identifier>DOI: 10.1083/jcb.201407129</identifier><identifier>PMID: 25825518</identifier><identifier>CODEN: JCLBA3</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>Apoptosis Regulatory Proteins - genetics ; Apoptosis Regulatory Proteins - metabolism ; Apoptosis Regulatory Proteins - ultrastructure ; Binding Sites ; Brain ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Carrier Proteins - ultrastructure ; Cell growth ; Cell Line ; Cell Proliferation - genetics ; Central Nervous System - blood supply ; Crystallography ; Crystallography, X-Ray ; Gene Expression ; Hemangioma, Cavernous, Central Nervous System - genetics ; Humans ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Membrane Proteins - ultrastructure ; Mutagenesis ; Neovascularization, Physiologic - genetics ; Paxillin - metabolism ; Protein Binding ; Protein Interaction Mapping ; Protein Structure, Tertiary ; Proteins ; Proteolysis ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins - ultrastructure ; RNA Interference ; RNA, Small Interfering ; Sequence Alignment</subject><ispartof>J. Cell Biol, 2015-03, Vol.208 (7), p.987-1001</ispartof><rights>2015 Draheim et al.</rights><rights>Copyright Rockefeller University Press Mar 30, 2015</rights><rights>2015 Draheim et al. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c442t-5f3f2536d4b804db043ac48d727a87788d3c561f99084a040f145efec1dd3e3e3</citedby><cites>FETCH-LOGICAL-c442t-5f3f2536d4b804db043ac48d727a87788d3c561f99084a040f145efec1dd3e3e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25825518$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1178471$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Draheim, Kyle M</creatorcontrib><creatorcontrib>Li, Xiaofeng</creatorcontrib><creatorcontrib>Zhang, Rong</creatorcontrib><creatorcontrib>Fisher, Oriana S</creatorcontrib><creatorcontrib>Villari, Giulia</creatorcontrib><creatorcontrib>Boggon, Titus J</creatorcontrib><creatorcontrib>Calderwood, David A</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation</title><title>J. Cell Biol</title><addtitle>J Cell Biol</addtitle><description>Mutations in the essential adaptor proteins CCM2 or CCM3 lead to cerebral cavernous malformations (CCM), vascular lesions that most frequently occur in the brain and are strongly associated with hemorrhagic stroke, seizures, and other neurological disorders. CCM2 binds CCM3, but the molecular basis of this interaction, and its functional significance, have not been elucidated. Here, we used x-ray crystallography and structure-guided mutagenesis to show that an α-helical LD-like motif within CCM2 binds the highly conserved "HP1" pocket of the CCM3 focal adhesion targeting (FAT) homology domain. By knocking down CCM2 or CCM3 and rescuing with binding-deficient mutants, we establish that CCM2-CCM3 interactions protect CCM2 and CCM3 proteins from proteasomal degradation and show that both CCM2 and CCM3 are required for normal endothelial cell network formation. However, CCM3 expression in the absence of CCM2 is sufficient to support normal cell growth, revealing complex-independent roles for CCM3.</description><subject>Apoptosis Regulatory Proteins - genetics</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Apoptosis Regulatory Proteins - ultrastructure</subject><subject>Binding Sites</subject><subject>Brain</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Carrier Proteins - ultrastructure</subject><subject>Cell growth</subject><subject>Cell Line</subject><subject>Cell Proliferation - genetics</subject><subject>Central Nervous System - blood supply</subject><subject>Crystallography</subject><subject>Crystallography, X-Ray</subject><subject>Gene Expression</subject><subject>Hemangioma, Cavernous, Central Nervous System - genetics</subject><subject>Humans</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Membrane Proteins - ultrastructure</subject><subject>Mutagenesis</subject><subject>Neovascularization, Physiologic - genetics</subject><subject>Paxillin - metabolism</subject><subject>Protein Binding</subject><subject>Protein Interaction Mapping</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins</subject><subject>Proteolysis</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins - ultrastructure</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering</subject><subject>Sequence Alignment</subject><issn>0021-9525</issn><issn>1540-8140</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpd0c1vFCEYBnBibOxaPXo1RC9epvI5sBeTZuNXUuNFz4SBd1zWGRiBVdu_XjZbN9aQQAi_PDDzIPSMkktKNH-9c8MlI1QQRdn6AVpRKUin2_4hWhHCaLeWTJ6jx6XsCCFCCf4InTOpmZRUr5DbbD6xrk0ch1ghW1dDirhUO4Qp3ELBdQsh4yWnCiFi-L1kKOVgbPR4gTyHWjBEnxqcgp1whPor5e94THm2h7Qn6Gy0U4Gnd-sF-vru7ZfNh-768_uPm6vrzgnBaidHPjLJey8GTYQfiODWCe0VU1YrpbXnTvZ0XK-JFpYIMlIhYQRHvefQxgV6c8xd9sMM3kGs2U5myWG2-cYkG8z9kxi25lv6aQTXQnHWAl4cA1KpwRQXKritSzGCq4ZS1RRt6NXdLTn92EOpZg7FwTTZCGlfDO17zVodQjT68j-6S_sc2z9oSnFJOelJU91RuZxKyTCeXkyJOXRsWsfm1HHzz__9zJP-Wyr_A03yos4</recordid><startdate>20150330</startdate><enddate>20150330</enddate><creator>Draheim, Kyle M</creator><creator>Li, Xiaofeng</creator><creator>Zhang, Rong</creator><creator>Fisher, Oriana S</creator><creator>Villari, Giulia</creator><creator>Boggon, Titus J</creator><creator>Calderwood, David A</creator><general>Rockefeller University Press</general><general>The Rockefeller University 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>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>OTOTI</scope><scope>5PM</scope></search><sort><creationdate>20150330</creationdate><title>CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation</title><author>Draheim, Kyle M ; 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Cell Biol</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Draheim, Kyle M</au><au>Li, Xiaofeng</au><au>Zhang, Rong</au><au>Fisher, Oriana S</au><au>Villari, Giulia</au><au>Boggon, Titus J</au><au>Calderwood, David A</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation</atitle><jtitle>J. Cell Biol</jtitle><addtitle>J Cell Biol</addtitle><date>2015-03-30</date><risdate>2015</risdate><volume>208</volume><issue>7</issue><spage>987</spage><epage>1001</epage><pages>987-1001</pages><issn>0021-9525</issn><eissn>1540-8140</eissn><coden>JCLBA3</coden><abstract>Mutations in the essential adaptor proteins CCM2 or CCM3 lead to cerebral cavernous malformations (CCM), vascular lesions that most frequently occur in the brain and are strongly associated with hemorrhagic stroke, seizures, and other neurological disorders. CCM2 binds CCM3, but the molecular basis of this interaction, and its functional significance, have not been elucidated. Here, we used x-ray crystallography and structure-guided mutagenesis to show that an α-helical LD-like motif within CCM2 binds the highly conserved "HP1" pocket of the CCM3 focal adhesion targeting (FAT) homology domain. By knocking down CCM2 or CCM3 and rescuing with binding-deficient mutants, we establish that CCM2-CCM3 interactions protect CCM2 and CCM3 proteins from proteasomal degradation and show that both CCM2 and CCM3 are required for normal endothelial cell network formation. However, CCM3 expression in the absence of CCM2 is sufficient to support normal cell growth, revealing complex-independent roles for CCM3.</abstract><cop>United States</cop><pub>Rockefeller University Press</pub><pmid>25825518</pmid><doi>10.1083/jcb.201407129</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | J. Cell Biol, 2015-03, Vol.208 (7), p.987-1001 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Apoptosis Regulatory Proteins - genetics Apoptosis Regulatory Proteins - metabolism Apoptosis Regulatory Proteins - ultrastructure Binding Sites Brain Carrier Proteins - genetics Carrier Proteins - metabolism Carrier Proteins - ultrastructure Cell growth Cell Line Cell Proliferation - genetics Central Nervous System - blood supply Crystallography Crystallography, X-Ray Gene Expression Hemangioma, Cavernous, Central Nervous System - genetics Humans Membrane Proteins - genetics Membrane Proteins - metabolism Membrane Proteins - ultrastructure Mutagenesis Neovascularization, Physiologic - genetics Paxillin - metabolism Protein Binding Protein Interaction Mapping Protein Structure, Tertiary Proteins Proteolysis Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins - ultrastructure RNA Interference RNA, Small Interfering Sequence Alignment |
| title | CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation |
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