The phosphorylation of presenilin proteins

The phosphorylation of presenilin (PS) proteins was initially analyzed in cultured cells overexpressing the respective proteins. These studies revealed that the homologous PS proteins are differentially phosphorylated in vivo. Fulllength PS2 was found to be constitutively phosphorylated on serine residues (1,2). In contrast, very little if any (1) or a variable phosphorylation (2) was observed for PS1. The familial Alzheimer's disease (FAD) mutations tested, the A246E mutation of PS1 and the N141I mutation (volga german) of PS2, apparently have no effect on the differential phosphorylation of PS1 and PS2 (1). Because both PS proteins appeared to reside predominantly within the endoplasmic reticulum (1-4) differential phosphorylation is not due to distinct subcellular localizations of these proteins. Instead, the differential phosphorylation seems to be determined by structural differences between PS1 and PS2. The phosphorylation of full-length PS2 was localized to its N-terminal domain preceding the first transmembrane region (1). Although both PS proteins are highly homologous (5-7), their N-terminal domains differ in the primary structure. PS2 contains a stretch of acidic residues (amino acids 1-20), which is lacking in PS1 Fig. 1). This acidic domain of PS2 contains three consensus sites for casein kinases (CK), one site for CK-1 (serine 19) and two for CK-2 (serines 7 and 9; Fig. 1). Mutagenesis analyzes demonstrated that all three serine residues (serines 7, 9, and 19) are phosphorylated in cultured cells overexpressing PS2 (1). Moreover, in vitro phosphorylation demonstrated that the N-terminal domain of PS2 can be phosphorylated by both CK-1 and CK-2 (1). Thus, it is likely that full-length PS2 is phosphorylated by CK-1 and CK-2 in vivo within its N-terminal domain. The phosphorylated residues within the acidic region of PS2 precedes a PEST motif (8,9), which is lacking in PS1. PEST sequences have been shown to be implicated in the regulation of protein turnover, e.g., the degradation of proteins containing a PEST motif is enhanced (9). It will be of great interest to test whether the phosphorylation of PS2 influences its turnover.