title: Impas 1 possesses endoproteolytic activity against multipass membrane protein substrate cleaving the presenilin 1 holoprotein.
abstract: Presenilins (PS1 and PS2) are supposed to be unusual aspartic proteases and components of the gamma-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 gamma-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.
authors.affiliation: University of Massachusetts Medical School, Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, 303 Belmont Street, Worcester, MA 01604, USA.
authors.forename: Yuri K
authors.initials: YK
authors.lastname: Moliaka
authors.forename: Anastasia
authors.initials: A
authors.lastname: Grigorenko
authors.forename: Dmitri
authors.initials: D
authors.lastname: Madera
authors.forename: Evgeny I
authors.initials: EI
authors.lastname: Rogaev
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007962:Leukocytes; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D053764:Presenilin-1; D053766:Presenilin-2; D011480:Protease Inhibitors / Q000494:pharmacology; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D011480:Protease Inhibitors; D029701:Saccharomyces cerevisiae Proteins; D010450:Endopeptidases