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The Cell Adhesion Protein P-selectin Glycoprotein Ligand-1 Is a Substrate for the Aspartyl Protease BACE1
Abstract
The aspartyl protease BACE1 cleaves the amyloid precursor protein and the sialyltransferase ST6Gal I and is important in the pathogenesis of Alzheimer's disease. The normal function of BACE1 and additional physiological substrates have not been identified. Here we show that BACE1 acts on the P-selectin glycoprotein ligand 1 (PSGL-1), which mediates leukocyte adhesion in inflammatory reactions. In human monocytic U937 and human embryonic kidney 293 cells expressing endogenous or transfected BACE1, PSGL-1 was cleaved by BACE1 to generate a soluble ectodomain and a C-terminal transmembrane fragment. No evidence of the cleavage fragment was seen in primary cells derived from mice deficient in BACE1. By using deletion constructs and enzymatic deglycosylation of the C-terminal PSGL-1 fragments, the cleavage site in PSGL-1 was mapped to the juxtamembrane region within the ectodomain. In an in vitro assay BACE1 catalyzed the formation of the PSGL-1 products seen in vivo. The cleavage occurred at a Leu-Ser peptide bond as identified by mass spectrometry using a synthetic peptide. We conclude that PSGL-1 is an additional substrate for BACE1.
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Sialyltransferase and PSGL-1, in addition to APP and its homologues APLP1 and 2, are the only other reported substrates of BACE.
“Sialyltransferase and PSGL-1, in addition to APP and its homologues APLP1 and 2 are the only other reported substrates of BACE (6,43).”
From The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel β-Secretase (BACE1) Substrate (2005) · cites this paper as [43]
PSGL-1 is a BACE1 substrate that plays an important role in immune defenses by recruiting white blood cells to the site of infection.
“P‐selectin glycoprotein ligand‐1 (PSGL‐1) is a BACE1 substrate that plays an important role in immune defenses by recruiting white blood cells to the site of infection.”
From BACE1: More than just a β‐secretase (2022) · cites this paper as [25]
Nearly 70 BACE1 substrates have been identified to date.
“through secretome enrichment experiments, nearly 70 BACE1 substrates have been identified to date.”
From BACE1: More than just a β‐secretase (2022) · cites this paper as [25]
APP is a poor substrate for BACE1.
“It is well acknowledged that APP is a poor substrate for BACE1”
From BACE1: More than just a β‐secretase (2022) · cites this paper as [25]
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Prodomain processing of Asp1 (BACE2) is autocatalytic
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Metadata
- Authors
- Lichtenthaler, S. F., Dominguez, D.-I., Westmeyer, G. G., Reiss, K., Haass, C., Saftig, P., De Strooper, B., & Seed, B.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-12
- Volume
- 278
- Issue
- 49
- Pages
- 48713-48719
- ISSN
- 0021-9258
- Cited by
- 206
- References
- 2
- Language
- en
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