title: Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization.
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.
authors.affiliation: Department of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia; Centre of Excellence EN-FIST, Ljubljana, Slovenia;
authors.forename: Monika
authors.initials: M
authors.lastname: Avbelj
authors.affiliation: Department of Immunology, University of Tübingen, Tübingen, Germany;
authors.forename: Olaf-Oliver
authors.initials: OO
authors.lastname: Wolz
authors.affiliation: Department of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia;
authors.forename: Ota
authors.initials: O
authors.lastname: Fekonja
authors.affiliation: Department of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia; Centre of Excellence EN-FIST, Ljubljana, Slovenia;
authors.forename: Mojca
authors.initials: M
authors.lastname: Benčina
authors.affiliation: Laboratory for Biocomputing and Bioinformatics, National Institute of Chemistry, Ljubljana, Slovenia; and.
authors.forename: Matej
authors.initials: M
authors.lastname: Repič
authors.affiliation: Laboratory for Biocomputing and Bioinformatics, National Institute of Chemistry, Ljubljana, Slovenia; and.
authors.forename: Janez
authors.initials: J
authors.lastname: Mavri
authors.affiliation: Center for Bioinformatics Tübingen, University of Tübingen, Tübingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Krüger
authors.affiliation: Center for Bioinformatics Tübingen, University of Tübingen, Tübingen, Germany.
authors.forename: Charlotta
authors.initials: C
authors.lastname: Schärfe
authors.affiliation: Department of Immunology, University of Tübingen, Tübingen, Germany;
authors.forename: Magno
authors.initials: M
authors.lastname: Delmiro Garcia
authors.affiliation: Department of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia; Centre of Excellence EN-FIST, Ljubljana, Slovenia;
authors.forename: Gabriela
authors.initials: G
authors.lastname: Panter
authors.affiliation: Center for Bioinformatics Tübingen, University of Tübingen, Tübingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kohlbacher
authors.affiliation: Department of Immunology, University of Tübingen, Tübingen, Germany;
authors.forename: Alexander N R
authors.initials: AN
authors.lastname: Weber
authors.affiliation: Department of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia; Centre of Excellence EN-FIST, Ljubljana, Slovenia;
authors.forename: Roman
authors.initials: R
authors.lastname: Jerala
mesh_terms: D000495:Allosteric Site; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D007249:Inflammation; D049449:Luminescence; D008223:Lymphoma / Q000235:genetics*; D018613:Microscopy, Confocal; D056004:Molecular Dynamics Simulation; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1