Proteolytic Fragments of the Alzheimer's Disease Associated Presenilins-1 and -2 Are Phosphorylated in Vivo by Distinct Cellular Mechanisms†

摘要: The majority of familial Alzheimer's disease mutations are linked to the recently cloned presenilin (PS) genes, which encode two highly homologous proteins (PS-1 and PS-2). Full-length PS undergo endoproteolytic cleavage within their hydrophilic loop domain resulting in formation C-terminal (CTF) N-terminal fragments (NTF). PS-2 was found be phosphorylated as a full-length protein its domain. In contrast, PS-1 is selectively after proteolytic processing approximately 20 kDa CTF involving kinase C (PKC) and/or A (PKA). We now have that also phosphorylated. Surprisingly, not by PKC or PKA. Instead, constitutively vivo serine/threonine kinases, independent phorbol ester intracellular cAMP. vitro large between transmembrane domains 6 7 can casein kinase-1 (CK-1) CK-2, but PKA PKC. Quantitative analysis phosphorylation demonstrates presence sites for CK-1 single site CK-2. deletion revealed an acidic sequence containing three potential CKs (serines 327, 330, 335). These data suggest CK type kinases phosphorylate vivo. Interestingly, located directly adjacent identified caspase sites.