Overall Architecture of PIKK Family Proteins

Figure 1 illustrates the domain architecture of the PIKK family. The PIKK kinase domain is located within the carboxy-terminal, « 400-amino-acid residues of these proteins, with the exception of hSMG-1, whose kinase domain lies more centrally within the polypeptide. Consistent with the crystal structure of the kinase domain of porcine PI3K (p110y), which shows gross overall structural similarity to the structures of classical protein Ser/Thr kinases [15], the kinase domains of PIKK family members generally contain residues that can be aligned with those playing key roles in adenosine triphosphate (ATP) coordination in other classes of kinase. A notable exception to this is TRRAP, which does not contain the DXXXXN and DFG motifs that are critical for ATP coordination within a kinase catalytic site [11]. The available data suggest that this renders the kinase domain of TRRAP catalytically inactive [14]. Nevertheless, the significant sequence homology between the C-terminal region of TRRAP and other members of the PIKK family suggests that this region of TRRAP will retain the overall structural features of the PIKK kinase domain.

In all cases, the kinase active site of PIKK family proteins is flanked N-terminally by a region of « 500-amino-acid residues, which has been named the FAT domain (derived from FRAP, ATM, and TRRAP) and C-terminally by a small (« 35-amino-acid residue) FAT C-terminal (FAT-C) domain [16]. To date, FAT and FAT-C domains have only been found in proteins in combination. No function has been ascribed to these domains but they could be involved in intermolecular protein-protein interactions. Alternatively, they could modulate kinase activity either by intramolecular interactions with the PIKK kinase domain or by binding kinase substrates and thus bringing them into the proximity of the ATP binding site. Notably, the FAT-C domain found in SMG-1 is separated from the kinase domain by almost 1200 amino acid residues. Nevertheless, it is possible that these regions come together in the protein tertiary structure [8].

In mTOR, conserved HEAT repeats are found in two groupings in the first half of the protein [9]. The HEAT repeat is a tandemly repeated module of 37 to 47 amino acid residues

Figure 1 The domain architecture of the PIKK family; human proteins are shown (see text for details).

occurring in a range of cytoplasmic proteins (which include the four proteins from which the acronym was derived: Huntingtin, EF3, the alpha regulatory subunit of PP2A, and TOR). These motifs may be involved in protein-protein interactions within multiprotein complexes [17]. The FRB (FKBP12-rapamycin binding) domain has so far been found only within the mTOR and SMG-1 sequences [8,9]. When bound to this region of mTOR, the FKBP12-rapamycin complex is able to inhibit mTOR function [9]. The crystal structure of this beta-barrel-like domain in a complex with the rapamycin-immunophilin complex has been solved [18]. Other than this clearly soluble and surface domain of mTOR, no truly distinct or soluble domains have so far been identified in other members of the PIKK family. Finally, a small region of homology between ATM and ATR upstream of the FAT domain has been noted [6].

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