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Matriptase processing of APLP1 ectodomain alters its homodimerization
Erwan Lanchec1, Antoine Désilets1, François Béliveau1
1Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, J1H5N4, Canada.
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.
Insights
Matriptase, a protease, directly cleaves amyloid-like protein 1 (APLP1) at arginine 124. This interaction disrupts APLP1 homodimeric interactions, impacting its functions.
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- Amyloid precursor protein (APP) processing by secretases produces amyloid beta peptide (Aβ).
- Matriptase, a serine protease, cleaves APP, influencing Aβ production.
- Amyloid-like protein 1 (APLP1) is an APP homolog with shared functional similarities.
Purpose of the Study:
- To investigate the role of matriptase in the processing of amyloid-like protein 1 (APLP1).
- To determine if matriptase interacts with and cleaves APLP1.
Main Methods:
- Cellular assays to demonstrate matriptase-APLP1 interaction.
- Site-directed mutagenesis (Arg124 to Ala) to assess cleavage site.
- Bioluminescence resonance energy transfer (BRET) assay to study APLP1 homodimeric interactions.
Main Results:
- Matriptase directly interacts with APLP1.
- APLP1 is cleaved by matriptase at arginine 124 within its E1 ectodomain.
- Mutation of Arg124 to Ala prevents matriptase-mediated cleavage of APLP1.
- Matriptase reduces APLP1 homodimeric interactions.
Conclusions:
- Matriptase is identified as the first protease to cleave APLP1.
- Cleavage occurs within the APLP1 dimerization domain.
- This cleavage may alter functions associated with APLP1 dimer formation.
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