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PMID: 16597736 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The GxGD motif of presenilin contributes to catalytic function and substrate identification of gamma-secretase.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 26 ·No. 14 ·2006-04-05 ·Pages 3821-8

Yamasaki A, Eimer S, Okochi M, Smialowska A, Kaether C, Baumeister R, Haass C, Steiner H

Abstract

Gamma-secretase is a multisubunit aspartyl protease complex that catalyzes intramembrane cleavage of beta-amyloid precursor protein (APP), a substrate key to Alzheimer's disease pathogenesis, and of Notch, a substrate crucial for cell differentiation. How gamma-secretase recognizes and selects substrates is currently barely understood. Recent data suggest that its subunit nicastrin serves as an initial substrate receptor, which might subsequently forward substrates to the active site domain located in its catalytic subunit presenilin (PS), where an additional substrate binding site has been proposed. We now used an active site domain swapping approach of PS1 with its most distant homolog, spermatogenesis defective (SPE-4), to identify sequence determinants in this region. Strikingly, when the active site domain of PS1 was exchanged with that of SPE-4, the chimeric protein, PS1/SPE-4(6/7), supported APP but not Notch processing. In addition, PS1/SPE-4(6/7) was strongly impaired in Caenorhabditis elegans Notch signaling in vivo. Mapping experiments identified a single amino acid at position x of the GxGD motif, which contains one of the two active site aspartates, to be responsible for the observed defect in Notch processing and signaling. Our data thus implicate a role of the GxGD motif in catalytic function and substrate identification of gamma-secretase.

MeSH Terms
Amino Acid Motifs Amino Acid Substitution Amyloid Precursor Protein Secretases Animals Aspartic Acid Endopeptidases Binding Sites Catalysis Cells, Cultured Endopeptidases/chemistry,metabolism Enzyme Activation Fibroblasts/metabolism Membrane Proteins/chemistry,genetics,metabolism Mice Mutagenesis, Site-Directed Presenilin-1 Protein Binding Structure-Activity Relationship Substrate Specificity
Chemicals
Membrane Proteins Presenilin-1 Amyloid Precursor Protein Secretases Endopeptidases Aspartic Acid Endopeptidases Bace1 protein, mouse
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Yamasaki Aya
Laboratory for Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, 80336 Munich, Germany.
Eimer Stefan
Okochi Masayasu
Smialowska Agata
Kaether Christoph
Baumeister Ralf
Haass Christian
Steiner Harald
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.5354-05.2006
Published
2006-04-05
Pages
3821-8
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6674133
Subset
IM
External Links
PubMed source DOI: 10.1523/JNEUROSCI.5354-05.2006 PMC Full Text View journal details
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