Cooperative Domain Formation by Homologous Motifs in HOIL-1L and SHARPIN Plays A Crucial Role in LUBAC Stabilization

被引：82

作者：

Fujita, Hiroaki ^{[1
]}

Tokunaga, Akira ^{[2
]}

Shimizu, Satoshi ^{[3
]}

Whiting, Amanda L. ^{[4
]}

Aguilar-Alonso, Francisco ^{[4
]}

Takagi, Kenji ^{[5
]}

Walinda, Erik ^{[1
]}

Sasaki, Yoshiteru ^{[1
]}

Shimokawa, Taketo ^{[1
]}

Mizushima, Tsunehiro ^{[5
]}

Ohki, Izuru ^{[2
]}

Ariyoshi, Mariko ^{[2
,7
]}

Tochio, Hidehito ^{[6
]}

Bernal, Federico ^{[4
]}

Shirakawa, Masahiro ^{[2
]}

Iwai, Kazuhiro ^{[1
]}

机构：

[1] Kyoto Univ, Dept Mol & Cellular Physiol, Sch Med, Kyoto 6068501, Japan

[2] Kyoto Univ, Dept Mol Engn, Sch Engn, Kyoto 6158510, Japan

[3] Kyoto Univ Hosp, Dept Anesthesia, Kyoto 6068507, Japan

[4] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Frederick, MD 21702 USA

[5] Univ Hyogo, Dept Picobiol, Sch Life Sci, Kobe, Hyogo 6781297, Japan

[6] Kyoto Univ, Dept Biophys, Sch Sci, Kyoto 6068502, Japan

[7] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan

来源：

CELL REPORTS | 2018年 / 23卷 / 04期

关键词：

CHAIN ASSEMBLY COMPLEX; NF-KAPPA-B; CELL-DEATH; LINEAR UBIQUITINATION; ACTIVATION; BINDING; HOIP; INFLAMMATION; INVOLVEMENT; DEFICIENCY;

D O I：

10.1016/j.celrep.2018.03.112

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The linear ubiquitin chain assembly complex (LUBAC) participates in inflammatory and oncogenic signaling by conjugating linear ubiquitin chains to target proteins. LUBAC consists of the catalytic HOIP subunit and two accessory subunits, HOIL-1L and SHARPIN. Interactions between the ubiquitin-associated (U BA) domains of HOIP and the ubiquitin-like (UBL) domains of two accessory subunits are involved in LUBAC stabilization, but the precise molecular mechanisms underlying the formation of stable trimeric LUBAC remain elusive. We solved the co-crystal structure of the binding regions of the trimeric LUBAC complex and found that LUBAC-tethering motifs (LTMs) located N terminally to the UBL domains of HOIL-1L and SHARPIN heterodimerize and fold into a single globular domain. This interaction is resistant to dissociation and plays a critical role in stabilizing trimeric LUBAC. Inhibition of LTM-mediated HOIL1L/SHARPIN dimerization profoundly attenuated the function of LUBAC, suggesting LTM as a superior target of LUBAC destabilization for anticancer therapeutics.

引用

页码：1192 / 1204

页数：13

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