Abstract
Alzheimer's disease (AD)-associated gamma-secretase is a presenilin (PS)- dependent proteolytic activity involved in the intramembraneous cleavage of the beta-amyloid precursor protein, Notch, LDL receptor-related protein, E-cadherin, and ErbB-4. This cut produces the corresponding intracellular domains (ICD), which are required for nuclear signaling of Notch and probably ErbB-4, the beta-amyloid precursor protein, E-cadherin, and the LDL receptor-related protein as well. We have now investigated CD44, a cell surface adhesion molecule, which also undergoes an intramembraneous cleavage to liberate its ICD. We demonstrate that this cleavage requires a PS-dependent gamma-secretase activity. A loss-of-function PS1 mutation, a PS1/PS2 knockout, as well as two independent and highly specific gamma-secretase inhibitors, abolish this cleavage. Surprisingly, small peptides similar to the amyloid beta-peptide (Abeta) are generated by an additional cut in the middle of the transmembrane region of CD44. Like Abeta, these CD44 beta-peptides are generated in a PS-dependent manner. These findings therefore suggest a dual intramembraneous cleavage mechanism mediated by PS proteins. The dual cleavage mechanism is required for nuclear signaling as well as removal of remaining transmembrane domains, a general function of PS in membrane protein metabolism.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alzheimer Disease / metabolism
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Amino Acid Sequence
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Amyloid Precursor Protein Secretases
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism
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Animals
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Aspartic Acid Endopeptidases / metabolism
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Carbamates / pharmacology
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Cell Line
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Cell Membrane / metabolism*
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Dipeptides / pharmacology
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Endopeptidases / metabolism*
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Enzyme Inhibitors / pharmacology
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Humans
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / metabolism*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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Molecular Sequence Data
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Peptides / genetics
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Peptides / metabolism*
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Presenilin-1
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Presenilin-2
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Protein Structure, Tertiary
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Sequence Alignment
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Triglycerides / pharmacology
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gamma-Aminobutyric Acid / analogs & derivatives*
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gamma-Aminobutyric Acid / pharmacology
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Carbamates
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Dipeptides
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Enzyme Inhibitors
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Hyaluronan Receptors
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L 685458
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Membrane Proteins
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PSEN1 protein, human
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PSEN2 protein, human
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Peptides
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Presenilin-1
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Presenilin-2
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Triglycerides
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gamma-Aminobutyric Acid
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1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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Bace1 protein, mouse