Structural and Functional Insights into GID/CTLH E3 Ligase Complexes

Abstract

Multi-subunit E3 ligases facilitate ubiquitin transfer by coordinating various substrate receptor subunits with a single catalytic center. Small molecules inducing targeted protein degradation have exploited such complexes, proving successful as therapeutics against previously undruggable targets. The C-terminal to LisH (CTLH) complex, also called the glucose-induced degradation deficient (GID) complex, is a multi-subunit E3 ligase complex highly conserved from Saccharomyces cerevisiae to humans, with roles in fundamental pathways controlling homeostasis and development in several species. However, we are only beginning to understand its mechanistic basis. Here, we review the literature of the CTLH complex from all organisms and place previous findings on individual subunits into context with recent breakthroughs on its structure and function.

A chemical probe to modulate human GID4 Pro/N-degron interactions

“…The cellular activity and specific target engagement by PFI-7 is evident from the robust changes observed in GID4 interactions and proteome level regulation. Since the E3 ligase activity of the human CTLH complex has only recently been demonstrated 18,20 , and it is unclear what role GID4-mediated substrate recruitment and proteasomal degradation plays in the array of fundamental cellular processes the complex has been implicated in 12 we analyzed global proteomics and the interactome of GID4 in the presence and absence of PFI-7 to probe the function of GID4 and the CTLH complex. We demonstrate that several proteins such as RNA helicases DDX21 and DDX50 are recognized by GID4 but are not substantively regulated at the protein level.…”

“…1A) 11 . Notable differences between the yeast and human complexes have been observed 12 . In S. cerevisiae, Gid4 is interchangeable with other substrate receptors including Gid10 and Gid11 [13][14][15] , while GID4 is thus far the only CTLH complex substrate receptor identified in humans, despite some substrates being degraded in a GID4 independent manner 16 .…”

“…In S. cerevisiae, Gid4 is interchangeable with other substrate receptors including Gid10 and Gid11 [13][14][15] , while GID4 is thus far the only CTLH complex substrate receptor identified in humans, despite some substrates being degraded in a GID4 independent manner 16 . In humans, the CTLH complex is implicated in a wide variety of cellular processes including autophagy, development, cell cycle regulation, and primary cilium function 12 . Mutations in, and over expression of CTLH complex members are also common in some cancers 17 .…”

Chemical tools for the Gid4 subunit of the human E3 ligase C-terminal to LisH (CTLH) degradation complex

“…4 Much of the understanding of Gid4 comes from its role in yeast biology, and the behavior of its human ortholog found within the CTLH complex remains somewhat extrapolated from there. 5 In response to changes in environmental glucose, yeast undergo a rapid switch from gluconeogenic to glycolytic processes. 6 This metabolic change is enabled, in part, through targeted protein degradation of gluconeogenic enzymes conducted by the multi-subunit E3 ligase GID (glucose-induced degradation) complex.…”

Skraban‐Deardorff intellectual disability syndrome‐associated mutations in WDR26 impair CTLH E3 complex assembly

“…The CTLH E3 is the mammalian orthologue of the Saccharomyces cerevisiae glucose-induced degradation deficient (GID) complex [9]. Both the CTLH and GID E3 complexes refer to a collection of various large multiprotein assemblies that target specific proteins for degradation [10][11][12][13][14]. The best understood members of the GID/CTLH E3 family are from S. cerevisiae.…”