Cell Reports
Volume 23, Issue 4, 24 April 2018, Pages 1192-1204
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Article
Cooperative Domain Formation by Homologous Motifs in HOIL-1L and SHARPIN Plays A Crucial Role in LUBAC Stabilization

https://doi.org/10.1016/j.celrep.2018.03.112Get rights and content
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Highlights

  • The crystal structure of trimeric LUBAC core solved at 2.4 Å resolution

  • Formation of a single domain by HOIL-1L and SHARPIN stabilizes LUBAC

  • Targeting the HOIL-1L/SHARPIN interaction efficiently disrupts LUBAC

  • Loss of the HOIL-1L UBL in mice leads to embryonic lethality

Summary

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.

Keywords

linear ubiquitin chains
LUBAC
LUBAC-tethering motif
HOIP
HOIL-1L
SHARPIN
ubiquitin-like domain
ubiquitin-associated domain
cancer

Cited by (0)

7

These authors contributed equally

8

Present address: Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan

9

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