Impas 1 possesses endoproteolytic activity against multipass membrane protein substrate cleaving the presenilin 1 holoprotein

FEBS Letters

Madera, Dmitri¹  Grigorenko, Anastasia¹  Rogaev, Evgeny I¹  Moliaka, Yuri K¹ 

[1] University of Massachusetts Medical School, Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, 303 Belmont Street, Worcester, MA 01604, USA

关键词: Presenilins;    Protease;    Intramembrane proteolysis;    Transmembrane precursor proteins;    IMPAS;    Alzheimer's disease;    Expression;    Mammalian cells;    Ab;    antibody;    AD;    Alzheimer's disease;    APP;    amyloid precursor protein;    chr;    chromosome;    CTF;    carboxy-terminal fragment;    DMSO;    dimethyl sulfoxide;    HD;    hydrophobic domain;    HEK;    human embryonic kidney;    IMP;    intramembrane protease-associated or intramembrane protease aspartic protein;    IMPAS;    family of these proteins;    NTF;    N-terminal fragment;    PS;    presenilin;    SPP;    signal peptide peptidase;    wt;    wild type;   

DOI  :  10.1016/S0014-5793(03)01489-3

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown