Abstract
The members of the phosphatidylinositol 3-kinase-related kinase (PIKK) family play vital roles in multiple biological processes, including DNA damage response, metabolism, cell growth, mRNA decay, and transcription. TRRAP, as the only member lacking the enzymatic activity in this family, is an adaptor protein for several histone acetyltransferase (HAT) complexes and a scaffold protein for multiple transcription factors. TRRAP has been demonstrated to regulate various cellular functions in cell cycle progression, cell stemness maintenance and differentiation, as well as neural homeostasis. TRRAP is known to be an important orchestrator of many molecular machineries in gene transcription by modulating the activity of some key transcription factors, including E2F1, c-Myc, p53, and recently, Sp1. This review summarizes the biological and biochemical studies on the action mode of TRRAP together with the transcription factors, focusing on how TRRAP-HAT mediates the transactivation of Sp1-governing biological processes, including neurodegeneration.
Highlights
The members of the phosphatidylinositol 3-kinase-related kinase (PIKK) family play vital roles in multiple biological processes, including DNA damage response, metabolism, cell growth, mRNA decay, and transcription
Phosphatidylinositol 3-kinase-related kinases (PIKK) are a protein family consisting of six serine/threonine protein kinases that transfer signals to a variety of protein substrates to control multiformities of biological processes
Lysine acetylation on histonean tails leads toco-activator the relaxation of chromatin structure, studies showed that all orthologs and paralogs of lack granting accessibility of transcription factors (TFs) and transcription machinery to thethe enzymatic activity
Summary
Phosphatidylinositol 3-kinase-related kinases (PIKK) are a protein family consisting of six serine/threonine protein kinases that transfer signals to a variety of protein substrates to control multiformities of biological processes. PIKK members share a structural commonality and identity in protein domains. The catalytic domain shares homology between the PIKK and the PI3K family, the PIKK catalytic motif varies from. PI3K in the structure of the ATP-binding motif, VAIK, and the divalent cation-binding motif, DFG. PIKKs are not involved in lipid phosphorylation, as is the major task of PI3K [1] (Figure 1). The kinase domain without its catalytic activity, if conserved throughout evolution, is considered the fundamental importance of the non-catalytic function of the protein [6]. 2021, 22, 12445 like kinase domain in TRRAP: the ATP-binding motif VAIK, the catalytic motif HRD, and the divalent cation-binding motif (DFG) [7,8]. TRRAP/Tra is highly conserved through the eukaryotic clades and considered it as the ancestral member of the PIKK family [1]
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