New insights into the evolutionary conservation of the sole PIKK pseudokinase Tra1/TRRAP

Abstract

Phosphorylation by protein kinases is a fundamental mechanism of signal transduction. Many kinase families contain one or several members that, although evolutionarily conserved, lack the residues required for catalytic activity. Studies combining structural, biochemical, and functional approaches revealed that these pseudokinases have crucial roles in vivo and may even represent attractive targets for pharmacological intervention. Pseudokinases mediate signal transduction by a diversity of mechanisms, including allosteric regulation of their active counterparts, assembly of signaling hubs, or modulation of protein localization. One such pseudokinase, named Tra1 in yeast and transformation/transcription domain-associated protein (TRRAP) in mammals, is the only member lacking all catalytic residues within the phosphatidylinositol 3-kinase related kinase (PIKK) family of kinases. PIKKs are related to the PI3K family of lipid kinases, but function as Serine/Threonine protein kinases and have pivotal roles in diverse processes such as DNA damage sensing and repair, metabolic control of cell growth, nonsense-mediated decay, or transcription initiation. Tra1/TRRAP is the largest subunit of two distinct transcriptional co-activator complexes, SAGA and NuA4/TIP60, which it recruits to promoters upon transcription factor binding. Here, we review our current knowledge on the Tra1/TRRAP pseudokinase, focusing on its role as a scaffold for SAGA and NuA4/TIP60 complex assembly and recruitment to chromatin. We further discuss its evolutionary history within the PIKK family and highlight recent findings that reveal the importance of molecular chaperones in pseudokinase folding, function, and conservation.

Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity

“…Family members of phosphatidylinositol 3-kinase-related kinases (PIKKs) activate distinct signaling pathways that promote cellular survival in different environmental and endogenous stress conditions ( Baretić and Williams, 2014 ; Imseng et al, 2018 ; Lempiäinen and Halazonetis, 2009 ). Specifically, PIKKs oversee translation machinery in the cytoplasm (mTOR, SMG1), or regulate DNA damage repair in the nucleus (ATM, ATR and DNA-PK) ( Shimobayashi and Hall, 2014 ; Saxton and Sabatini, 2017 ; Yamashita, 2013 ; Yamashita et al, 2001 ; Blackford and Jackson, 2017 ; Elías-Villalobos et al, 2019 ). With the exception of the enzymatically inactive TRAPP/Tra1, which serves as a scaffold in chromatin modification complexes, all other members of the PIKK family are Ser/Thr-protein kinases, and are among the largest proteins in the eukaryotic kinome.…”

The TRRAP transcription cofactor represses interferon-stimulated genes in colorectal cancer cells

“…TRRAP regulates transcription as part of either the TIP60 or the SAGA co-activator complex (30). We thus asked whether SAGA and TIP60 contribute to ISG repression in HCT116 cells.…”

“…TRRAP is an evolutionary conserved member of an atypical family of kinases, called phosphoinositide 3 kinase-related kinases (PIKK), with which it shares a characteristic domain architecture. However, TRRAP lacks all catalytic residues and is therefore the sole pseudokinase of this family (reviewed in (30)). Active PIKKs are implicated in diverse processes.…”

“…Active PIKKs are implicated in diverse processes. ATM, ATR, and DNA-PKcs control DNA repair and telomere homeostasis, mTOR modulates cell growth, proliferation, and survival in response to metabolic inputs, and SMG-1 mediates nonsense-mediated mRNA decay (30,31). Elegant studies have demonstrated that PIKKs require a dedicated HSP90 co-chaperone, the triple T complex (TTT), for their stabilization and incorporation into active complexes (32)(33)(34)(35)(36)(37).…”

The SAGA and NuA4 component Tra1 regulates Candida albicans drug resistance and pathogenesis

“…Tra1/TRRAP is an essential component of SAGA and NuA4 complexes (35)(36)(37). It is a member of the PIKK (phosphoinositide-3-kinase-related kinase) family that also includes Tor1, ATM and Rad3-related protein (ATR/Mec1), and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) (38).…”