A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b.
Gamma-secretase and signal peptide peptidase (SPP) are unusual GxGD aspartyl proteases, which mediate intramembrane proteolysis. In addition to SPP, a family of SPP-like proteins (SPPLs) of unknown function has been identified. We demonstrate that SPPL2b utilizes multiple intramembrane cleavages to liberate the intracellular domain of tumor necrosis factor alpha (TNFalpha) into the cytosol and the carboxy-terminal counterpart into the extracellular space. These findings suggest common principles for regulated intramembrane proteolysis by GxGD aspartyl proteases.
Fluhrer
Regina
R
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig Maximilians University, 80336 Munich, Germany.
Grammer
Gudula
G
Israel
Lars
L
Condron
Margaret M
MM
Haffner
Christof
C
Friedmann
Elena
E
Böhland
Claudia
C
Imhof
Axel
A
Martoglio
Bruno
B
Teplow
David B
DB
Haass
Christian
C
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D003600:Cytosol / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D029961:Zebrafish Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C460085:signal peptide peptidase; C513920:sppl2 protein, zebrafish; C509280:BACE1 protein, human