Structural Insights into SHARPIN-Mediated Activation of HOIP for the Linear Ubiquitin Chain Assembly

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Jianping Liu, Yingli Wang, Yukang Gong, Tao Fu, Shichen Hu, Zixuan Zhou, Lifeng Pan
The linear ubiquitin chain assembly complex (LUBAC) is the sole identified E3 ligase complex that catalyzes the formation of linear ubiquitin chain, and it is composed of HOIP, HOIL-1L, and SHARPIN. The E3 activity of HOIP can be effectively activated by HOIL-1L or SHARPIN, deficiency of which leads to severe immune system disorders. However, the underlying mechanism governing the HOIP-SHARPIN interaction and the SHARPIN-mediated activation of HOIP remains elusive. Here, we biochemically and structurally demonstrate that the UBL domain of SHARPIN specifically binds to the UBA domain of HOIP and thereby associates with and activates HOIP. We further uncover that SHARPIN and HOIL-1L can separately or synergistically bind to distinct sites of HOIP UBA with induced allosteric effects and thereby facilitate the E2 loading of HOIP for its activation. Thus, our findings provide mechanistic insights into the assembly and activation of LUBAC.

Graphical abstract

Teaser

LUBAC mediates the formation of linear ubiquitin chains and plays critical roles in numerous signaling pathways. Liu et al. determine the crystal structure of HOIP in complex with SHARPIN and examine the molecular mechanism governing the interaction between two LUBAC components.


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