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American Society of Hematology, Blood, 26(124), p. 3896-3904, 2014

DOI: 10.1182/blood-2014-05-573188

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Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization

Journal article published in 2014 by Monika Avbelj, Olaf-Oliver Wolz, Ota Fekonja, M. Ben ina, Mojca Benčina, M. Repi, Matej Repič, Janez Mavri, Jens Krüger, Charlotta Pauline Irmgard Schärfe, Magno Delmiro Garcia, Gabriela Panter, Oliver Kohlbacher, Alexander N. R. Weber, Roman Jerala
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

MyD88 is the key signaling adapter of Toll-like and IL-1 receptors. Recurrent lymphoma-associated mutations, particularly Leu265Pro (L265P), within the MyD88 TIR domain sustain lymphoma cell survival due to constitutive NF-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 domain. Blocking of MyD88 oligomerization induced apoptosis. The L265P TIR domain can recruit the endogenous WT MyD88 for oligomer formation and hyperactivity. Molecular dynamics simulations and analysis of additional mutations suggest that constitutive activity is caused by allosteric oligomerization.