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同源基序在 HOIL-1L 和 SHARPIN 中的合作结构域形成对于 LUBAC 的稳定起着至关重要的作用。

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

机构信息

Department of Molecular and Cellular Physiology, Kyoto University School of Medicine, Kyoto 606-8501, Japan.

Department of Molecular Engineering, Kyoto University School of Engineering, Kyoto 615-8510, Japan.

出版信息

Cell Rep. 2018 Apr 24;23(4):1192-1204. doi: 10.1016/j.celrep.2018.03.112.

DOI:10.1016/j.celrep.2018.03.112
PMID:29694895
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6044281/
Abstract

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 (UBA) 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 HOIL-1L/SHARPIN dimerization profoundly attenuated the function of LUBAC, suggesting LTM as a superior target of LUBAC destabilization for anticancer therapeutics.

摘要

线性泛素链组装复合物（LUBAC）通过将线性泛素链连接到靶蛋白上来参与炎症和致癌信号转导。LUBAC 由催化 HOIP 亚基和两个辅助亚基 HOIL-1L 和 SHARPIN 组成。HOIP 的泛素相关（UBA）结构域与两个辅助亚基的泛素样（UBL）结构域之间的相互作用参与了 LUBAC 的稳定，但稳定的三聚体 LUBAC 形成的确切分子机制仍不清楚。我们解析了三聚体 LUBAC 复合物结合区域的共晶结构，发现位于 HOIL-1L 和 SHARPIN 异二聚体 UBL 结构域 N 端的 LUBAC 连接基序（LTM）异源二聚化并折叠成单个球形结构域。这种相互作用不易解离，在稳定三聚体 LUBAC 中起着关键作用。抑制 LTM 介导的 HOIL-1L/SHARPIN 二聚化显著减弱了 LUBAC 的功能，这表明 LTM 作为 LUBAC 去稳定化的优越靶点，可用于癌症治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da7d/6044281/257b4ac824b9/nihms-975286-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da7d/6044281/ce1d9e1069d5/nihms-975286-f0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da7d/6044281/ec3c58629656/nihms-975286-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da7d/6044281/2eaa8734c163/nihms-975286-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da7d/6044281/d661539f2610/nihms-975286-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da7d/6044281/0dcacb912e96/nihms-975286-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da7d/6044281/257b4ac824b9/nihms-975286-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da7d/6044281/ce1d9e1069d5/nihms-975286-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da7d/6044281/221c346cf4df/nihms-975286-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da7d/6044281/ec3c58629656/nihms-975286-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da7d/6044281/2eaa8734c163/nihms-975286-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da7d/6044281/d661539f2610/nihms-975286-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da7d/6044281/0dcacb912e96/nihms-975286-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da7d/6044281/257b4ac824b9/nihms-975286-f0008.jpg

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