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

被引：66

作者：

Avbelj, Monika ^{[1
,2
]}

Wolz, Olaf-Oliver ^{[3
]}

Fekonja, Ota ^{[1
]}

Bencina, Mojca ^{[1
,2
]}

Repic, Matej ^{[4
]}

Mavri, Janez ^{[4
]}

Krueger, Jens ^{[5
]}

Schaerfe, Charlotta ^{[5
]}

Garcia, Magno Delmiro ^{[3
]}

Panter, Gabriela ^{[1
,2
]}

Kohlbacher, Oliver ^{[5
]}

Weber, Alexander N. R. ^{[3
]}

Jerala, Roman ^{[1
,2
]}

机构：

[1] Natl Inst Chem, Dept Biotechnol, Ljubljana 1000, Slovenia

[2] Ctr Excellence EN FIST, Ljubljana, Slovenia

[3] Univ Tubingen, Dept Immunol, Tubingen, Germany

[4] Natl Inst Chem, Lab Biocomp & Bioinformat, Ljubljana 1000, Slovenia

[5] Univ Tubingen, Ctr Bioinformat Tubingen, Tubingen, Germany

来源：

BLOOD | 2014年 / 124卷 / 26期

关键词：

TOLL/INTERLEUKIN-1 RECEPTOR DOMAIN; TOLL-LIKE RECEPTORS; CRYSTAL-STRUCTURE; SIGNAL-TRANSDUCTION; CYTOPLASMIC DOMAIN; STRUCTURAL BASIS; ADAPTER PROTEIN; CELLS; IDENTIFICATION; INHIBITION;

D O I：

10.1182/blood-2014-05-573188

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 kappa B 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.

引用

页码：3896 / 3904

页数：9

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