Cleavage of p75 neurotrophin receptor by alpha-secretase and gamma-secretase requires specific receptor domains

Item Type:	Article
Title:	Cleavage of p75 neurotrophin receptor by alpha-secretase and gamma-secretase requires specific receptor domains
Creators Name:	Zampieri, N. and Xu, C.F. and Neubert, T.A. and Chao, M.V.
Abstract:	The p75 neurotrophin receptor (p75(NTR)), a member of the tumor necrosis factor superfamily of receptors, undergoes multiple proteolytic cleavage events. These events are initiated by an alpha-secretase-mediated release of the extracellular domain followed by a gamma-secretase-mediated intramembrane cleavage. However, the specific determinants of p75(NTR) cleavage events are unknown. Many other substrates of gamma-secretase cleavage have been identified, including Notch, amyloid precursor protein, and ErbB4, indicating there is broad substrate recognition by gamma-secretase. Using a series of deletion mutations and chimeric receptors of p75(NTR) and the related Fas receptor, we have identified domains that are essential for p75(NTR) proteolysis. The initial alpha-secretase cleavage was extracellular to the transmembrane domain. Unfortunately, deletion mutants were not capable of defining the requirements of ectodomain shedding. Although this cleavage is promiscuous with respect to amino acid sequence, its position with respect to the transmembrane domain is invariant. The generation of chimeric receptors exchanging different domains of noncleavable Fas receptor with p75(NTR), however, revealed that a discrete domain above the membrane is sufficient for efficient cleavage of p75(NTR). Mass spectrometric analysis confirmed the cleavage can occur with a truncated p75(NTR) displaying only 15 extracellular amino acids in the stalk region.
Keywords:	Amino Acids, Amino Acid Sequence, Amino Acid Sequence Homology , Amyloid beta-Protein Precursor, Amyloid Precursor Protein Secretases, Aspartic Acid Endopeptidases, Cell Line, Cell Membrane, Conditioned Culture Media, Endopeptidases, Epidermal Growth Factor Receptor, Gene Deletion, Mass Spectrometry, Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry, Membrane Proteins, Molecular Sequence Data, Mutation, Nerve Growth Factor Receptor, Notch Receptors, PC12 Cells, Plasmids, Protein Binding, Schwann Cells, Spinal Ganglia , Tertiary Protein Structure, Western Blotting , Animals, Rats
Source:	Journal of Biological Chemistry
ISSN:	0021-9258
Publisher:	American Society for Biochemistry and Molecular Biology
Volume:	280
Number:	15
Page Range:	14563-14571
Date:	15 April 2005
Official Publication:	https://doi.org/10.1074/jbc.M412957200
PubMed:	View item in PubMed

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