Premium
Impas 1 possesses endoproteolytic activity against multipass membrane protein substrate cleaving the presenilin 1 holoprotein
Author(s) -
Moliaka Yuri K,
Grigorenko Anastasia,
Madera Dmitri,
Rogaev Evgeny I
Publication year - 2004
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(03)01489-3
Subject(s) - presenilin , substrate (aquarium) , chemistry , microbiology and biotechnology , membrane , biochemistry , biophysics , biology , medicine , disease , alzheimer's disease , ecology
Presenilins (PS1 and PS2) are supposed to be unusual aspartic proteases and components of the γ‐secretase complex regulating cleavage of type I proteins. Multiple mutations in PS1 are a major cause of familial early‐onset Alzheimer's disease (AD). We and others recently identified PS‐related families of proteins (IMPAS/PSH/signal peptide peptidases (SPP)). The functions of these proteins are yet to be determined. We found that intramembrane protease‐associated or intramembrane protease aspartic protein Impas 1 (IMP1)/SPP induces intramembranous cleavage of PS1 holoprotein in cultured cells coexpressing these proteins. Mutations in evolutionary invariant sites in hIMP1 or specific γ‐secretase inhibitors abolish the hIMP1‐mediated endoproteolysis of PS1. In contrast, neither AD‐like mutations in hIMP1 nor in PS1 substrate abridge the PS1 cleavage. The data suggest that IMP1 is a bi‐aspartic polytopic protease capable of cleaving transmembrane precursor proteins. These data, to our knowledge, are a first observation that a multipass transmembrane protein or the integral protease per se may be a primary substrate for an intramembranous proteolysis.