Abstract
The amyloid beta peptide (Aβ) is derived from the amyloid precursor protein (APP) by secretase processing. APP is also cleaved by numerous other proteases, such as the type II transmembrane serine protease matriptase, with consequences on the production of Aβ. Because the APP homolog protein amyloid-like protein 1 (APLP1) shares similarities with APP, we sought to determine if matriptase also plays a role in its processing. Here, we demonstrate that matriptase directly interacts with APLP1 and that APLP1 is cleaved in cellulo by matriptase in its E1 ectodomains at arginine 124. Replacing Arg124 with Ala abolished APLP1 processing by matriptase. Using a bioluminescence resonance energy transfer (BRET) assay we found that matriptase reduces APLP1 homodimeric interactions. This study identifies matriptase as the first protease cleaving APLP1 in its dimerization domain, potentially altering the multiple functions associated with dimer formation.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a progressive and accelerated loss of neurons, leading to cognitive disorders and is currently the most common dementia[1]
Since the E1 domain is conserved among members of the amyloid precursor protein (APP) family and is important for dimerization, we investigated the possibility that matriptase cleaves APLP1 and alters the dimerization/heterodimerization process
Immunoblot analysis of cell lysates reveals that GFP-APLP1 is detected as a major 120 kDa form (Fig. 1B), whereas matriptase is detected as a doublet at 95 kDa, which reflects the presence of the full-length 855 amino acid protein and a constitutively processed form at glycine 14938–40
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a progressive and accelerated loss of neurons, leading to cognitive disorders and is currently the most common dementia[1]. APP and APLP1 are known to form homo- and heterodimers[17], which are in part dependent on the conserved E1 domain[18] These dimeric interactions occur at the plasma membrane on a single cell (cis interaction) and occur between transmembrane proteins of adjacent cells (trans interaction) 19–21. We have recently shown that matriptase mRNA is expressed in different regions of human brain, with an enrichment in neurons and that it is present at the protein level in differentiated neurons derived from human induced pluripotent stem cells (hiPSCs)[38]. Since the E1 domain is conserved among members of the APP family and is important for dimerization, we investigated the possibility that matriptase cleaves APLP1 and alters the dimerization/heterodimerization process
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