Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization
Myeloid differentiation 88 (MyD88) is the key signaling adapter of Toll-like and interleukin-1 receptors. Recurrent lymphoma-associated mutations, particularly Leu265Pro (L265P), within the MyD88 Toll/interleukin-1 receptor (TIR) domain sustain lymphoma cell survival due to constitutive nuclear fact...
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| Veröffentlicht in: | Blood 2014-12, Vol.124 (26), p.3896-3904 |
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| creator | Avbelj, Monika Wolz, Olaf-Oliver Fekonja, Ota Benčina, Mojca Repič, Matej Mavri, Janez Krüger, Jens Schärfe, Charlotta Delmiro Garcia, Magno Panter, Gabriela Kohlbacher, Oliver Weber, AlexanderN. R. Jerala, Roman |
| description | Myeloid differentiation 88 (MyD88) is the key signaling adapter of Toll-like and interleukin-1 receptors. Recurrent lymphoma-associated mutations, particularly Leu265Pro (L265P), within the MyD88 Toll/interleukin-1 receptor (TIR) domain sustain lymphoma cell survival due to constitutive nuclear factor κB signaling. We found that mutated TIR domains displayed an intrinsic propensity for augmented oligomerization and spontaneous formation of cytosolic Myddosome aggregates in lymphoma cell lines, mimicking the effect of dimerized TIR domains. Blocking of MyD88 oligomerization induced apoptosis. The L265P TIR domain can recruit the endogenous wild-type MyD88 for oligomer formation and hyperactivity. Molecular dynamics simulations and analysis of additional mutations suggest that constitutive activity is caused by allosteric oligomerization.
•The hyperactive phenotype of lymphoma-associated mutations is caused by increased oligomerization propensity of the MyD88 TIR domain.•The TIR domain of mutants interacts with wild-type MyD88, explaining why heterozygous mutation could be sufficient as a driver mutation. |
| doi_str_mv | 10.1182/blood-2014-05-573188 |
| format | Article |
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•The hyperactive phenotype of lymphoma-associated mutations is caused by increased oligomerization propensity of the MyD88 TIR domain.•The TIR domain of mutants interacts with wild-type MyD88, explaining why heterozygous mutation could be sufficient as a driver mutation.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2014-05-573188</identifier><identifier>PMID: 25359991</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Allosteric Site ; Cell Line, Tumor ; HEK293 Cells ; Heterozygote ; Humans ; Immunobiology ; Inflammation ; Luminescence ; Lymphoma - genetics ; Microscopy, Confocal ; Molecular Dynamics Simulation ; Mutation ; Myeloid Differentiation Factor 88 - genetics ; Phenotype ; Polymerase Chain Reaction ; Protein Structure, Tertiary ; Receptors, Interleukin-1 - metabolism ; RNA, Small Interfering - metabolism ; Signal Transduction</subject><ispartof>Blood, 2014-12, Vol.124 (26), p.3896-3904</ispartof><rights>2014 American Society of Hematology</rights><rights>2014 by The American Society of Hematology.</rights><rights>2014 by The American Society of Hematology 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c529t-2eaf8348c99cc9936323edb56acbeefd96303d7e8c5905ffa64afbcb784aaf5f3</citedby><cites>FETCH-LOGICAL-c529t-2eaf8348c99cc9936323edb56acbeefd96303d7e8c5905ffa64afbcb784aaf5f3</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/25359991$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Avbelj, Monika</creatorcontrib><creatorcontrib>Wolz, Olaf-Oliver</creatorcontrib><creatorcontrib>Fekonja, Ota</creatorcontrib><creatorcontrib>Benčina, Mojca</creatorcontrib><creatorcontrib>Repič, Matej</creatorcontrib><creatorcontrib>Mavri, Janez</creatorcontrib><creatorcontrib>Krüger, Jens</creatorcontrib><creatorcontrib>Schärfe, Charlotta</creatorcontrib><creatorcontrib>Delmiro Garcia, Magno</creatorcontrib><creatorcontrib>Panter, Gabriela</creatorcontrib><creatorcontrib>Kohlbacher, Oliver</creatorcontrib><creatorcontrib>Weber, AlexanderN. R.</creatorcontrib><creatorcontrib>Jerala, Roman</creatorcontrib><title>Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization</title><title>Blood</title><addtitle>Blood</addtitle><description>Myeloid differentiation 88 (MyD88) is the key signaling adapter of Toll-like and interleukin-1 receptors. Recurrent lymphoma-associated mutations, particularly Leu265Pro (L265P), within the MyD88 Toll/interleukin-1 receptor (TIR) domain sustain lymphoma cell survival due to constitutive nuclear factor κB signaling. We found that mutated TIR domains displayed an intrinsic propensity for augmented oligomerization and spontaneous formation of cytosolic Myddosome aggregates in lymphoma cell lines, mimicking the effect of dimerized TIR domains. Blocking of MyD88 oligomerization induced apoptosis. The L265P TIR domain can recruit the endogenous wild-type MyD88 for oligomer formation and hyperactivity. Molecular dynamics simulations and analysis of additional mutations suggest that constitutive activity is caused by allosteric oligomerization.
•The hyperactive phenotype of lymphoma-associated mutations is caused by increased oligomerization propensity of the MyD88 TIR domain.•The TIR domain of mutants interacts with wild-type MyD88, explaining why heterozygous mutation could be sufficient as a driver mutation.</description><subject>Allosteric Site</subject><subject>Cell Line, Tumor</subject><subject>HEK293 Cells</subject><subject>Heterozygote</subject><subject>Humans</subject><subject>Immunobiology</subject><subject>Inflammation</subject><subject>Luminescence</subject><subject>Lymphoma - genetics</subject><subject>Microscopy, Confocal</subject><subject>Molecular Dynamics Simulation</subject><subject>Mutation</subject><subject>Myeloid Differentiation Factor 88 - genetics</subject><subject>Phenotype</subject><subject>Polymerase Chain Reaction</subject><subject>Protein Structure, Tertiary</subject><subject>Receptors, Interleukin-1 - metabolism</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Signal Transduction</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kctuFDEQRS0EIkPgDxDqJRuDH-0ee4MUJTwiJUJCYW257XJi5G4Ptnuk4etxZkJINlmUvKh7b5XrIPSWkg-USvZxjCk5zAjtMRFYrDmV8hlaUcEkJoSR52hFCBlwr9b0CL0q5RdpWs7ES3TEBBdKKbpC44mtYWtqSHOXfBd30-YmTQabUpINpoLrLndnUnbTUveq0m2D6UyMqVTIOxxmt9imujr_gV1zhpYTw3WaIIc_e8dr9MKbWODN3XuMfn75fHX6DV98_3p-enKBrWCqYgbGS95Lq5RtxQfOOLhRDMaOAN6pgRPu1iCtUER4b4be-NGOa9kb44Xnx-jTIXezjBM4C3PNJupNDpPJO51M0I87c7jR12mreyYZFbwFvL8LyOn3AqXqKRQLMZoZ0lI0HbjqpWJyaNL-ILU5lZLB34-hRN_i0Xs8-haPJkIf8DTbu4cr3pv-8fj_B2iH2gbIutgAcztwyGCrdik8PeEv3lOlqw</recordid><startdate>20141218</startdate><enddate>20141218</enddate><creator>Avbelj, Monika</creator><creator>Wolz, Olaf-Oliver</creator><creator>Fekonja, Ota</creator><creator>Benčina, Mojca</creator><creator>Repič, Matej</creator><creator>Mavri, Janez</creator><creator>Krüger, Jens</creator><creator>Schärfe, Charlotta</creator><creator>Delmiro Garcia, Magno</creator><creator>Panter, Gabriela</creator><creator>Kohlbacher, Oliver</creator><creator>Weber, AlexanderN. R.</creator><creator>Jerala, Roman</creator><general>Elsevier Inc</general><general>American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</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>20141218</creationdate><title>Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization</title><author>Avbelj, Monika ; Wolz, Olaf-Oliver ; Fekonja, Ota ; Benčina, Mojca ; Repič, Matej ; Mavri, Janez ; Krüger, Jens ; Schärfe, Charlotta ; Delmiro Garcia, Magno ; Panter, Gabriela ; Kohlbacher, Oliver ; Weber, AlexanderN. R. ; Jerala, Roman</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c529t-2eaf8348c99cc9936323edb56acbeefd96303d7e8c5905ffa64afbcb784aaf5f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Allosteric Site</topic><topic>Cell Line, Tumor</topic><topic>HEK293 Cells</topic><topic>Heterozygote</topic><topic>Humans</topic><topic>Immunobiology</topic><topic>Inflammation</topic><topic>Luminescence</topic><topic>Lymphoma - genetics</topic><topic>Microscopy, Confocal</topic><topic>Molecular Dynamics Simulation</topic><topic>Mutation</topic><topic>Myeloid Differentiation Factor 88 - genetics</topic><topic>Phenotype</topic><topic>Polymerase Chain Reaction</topic><topic>Protein Structure, Tertiary</topic><topic>Receptors, Interleukin-1 - metabolism</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Signal Transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Avbelj, Monika</creatorcontrib><creatorcontrib>Wolz, Olaf-Oliver</creatorcontrib><creatorcontrib>Fekonja, Ota</creatorcontrib><creatorcontrib>Benčina, Mojca</creatorcontrib><creatorcontrib>Repič, Matej</creatorcontrib><creatorcontrib>Mavri, Janez</creatorcontrib><creatorcontrib>Krüger, Jens</creatorcontrib><creatorcontrib>Schärfe, Charlotta</creatorcontrib><creatorcontrib>Delmiro Garcia, Magno</creatorcontrib><creatorcontrib>Panter, Gabriela</creatorcontrib><creatorcontrib>Kohlbacher, Oliver</creatorcontrib><creatorcontrib>Weber, AlexanderN. R.</creatorcontrib><creatorcontrib>Jerala, Roman</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</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>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Avbelj, Monika</au><au>Wolz, Olaf-Oliver</au><au>Fekonja, Ota</au><au>Benčina, Mojca</au><au>Repič, Matej</au><au>Mavri, Janez</au><au>Krüger, Jens</au><au>Schärfe, Charlotta</au><au>Delmiro Garcia, Magno</au><au>Panter, Gabriela</au><au>Kohlbacher, Oliver</au><au>Weber, AlexanderN. R.</au><au>Jerala, Roman</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2014-12-18</date><risdate>2014</risdate><volume>124</volume><issue>26</issue><spage>3896</spage><epage>3904</epage><pages>3896-3904</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>Myeloid differentiation 88 (MyD88) is the key signaling adapter of Toll-like and interleukin-1 receptors. Recurrent lymphoma-associated mutations, particularly Leu265Pro (L265P), within the MyD88 Toll/interleukin-1 receptor (TIR) domain sustain lymphoma cell survival due to constitutive nuclear factor κB signaling. We found that mutated TIR domains displayed an intrinsic propensity for augmented oligomerization and spontaneous formation of cytosolic Myddosome aggregates in lymphoma cell lines, mimicking the effect of dimerized TIR domains. Blocking of MyD88 oligomerization induced apoptosis. The L265P TIR domain can recruit the endogenous wild-type MyD88 for oligomer formation and hyperactivity. Molecular dynamics simulations and analysis of additional mutations suggest that constitutive activity is caused by allosteric oligomerization.
•The hyperactive phenotype of lymphoma-associated mutations is caused by increased oligomerization propensity of the MyD88 TIR domain.•The TIR domain of mutants interacts with wild-type MyD88, explaining why heterozygous mutation could be sufficient as a driver mutation.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>25359991</pmid><doi>10.1182/blood-2014-05-573188</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| language | eng |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Allosteric Site Cell Line, Tumor HEK293 Cells Heterozygote Humans Immunobiology Inflammation Luminescence Lymphoma - genetics Microscopy, Confocal Molecular Dynamics Simulation Mutation Myeloid Differentiation Factor 88 - genetics Phenotype Polymerase Chain Reaction Protein Structure, Tertiary Receptors, Interleukin-1 - metabolism RNA, Small Interfering - metabolism Signal Transduction |
| title | Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization |
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