Comparative Proteomics of the Conservation of BACE1 Substrates Across Species

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Comparative Proteomics of the Conservation of BACE1 Substrates Across Species

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In a world of modern medicine where people are living longer, Alzheimer’s disease (AD) is becoming increasingly relevant and problematic. As the number of people living with AD in the United States is greater than five million and increasing with each passing year, a better understanding of the disease mechanism is necessary to properly care for and treat these individuals. The beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is a membrane-bound aspartyl protease. It is responsible for cutting APP to form short β-amyloid (Aβ) peptides. The accumulation and aggregation of these peptides is a defining attribute of AD. Therefore, BACE1 has become a promising therapeutic target for the treatment and prevention of the disease. However, APP is not the only substrate cut by BACE1. Due to the importance of BACE1 as a potential target for AD treatment, it is imperative to fully understand its native function by identifying all possible substrates. In identifying such substrates, we hypothesize that native substrates (and the specific sequences) that are cleaved by BACE1 will be conserved throughout all species with BACE1 orthologs. In order to identify potential BACE1 substrates, the bioinformatics tools SignalP and TMHMM were used to identify all Type I membrane proteins (c-terminus of the protein is cytoplasmic) within a species’ proteome that have a single transmembrane domain since all known BACE1 substrates possess these characteristics. We describe our comparative analysis of the preferred BACE1 cut sites within these proteomes using published data about the enzymes preferred cut sequences. Analysis of the data from a variety of organisms showed the protein sequences cut by BACE1 were conserved. Having a better understanding of the identity of BACE1 substrates will be beneficial in identifying and reducing the side effects that may be present due to AD treatments that target this enzyme.


University Honors Capstone Project Paper, University of Minnesota Duluth, 2021. Department of Chemistry and Biochemistry.

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King, Shannon; Fritz, Meghan; Johnson, Joseph L. (2021). Comparative Proteomics of the Conservation of BACE1 Substrates Across Species. Retrieved from the University Digital Conservancy,

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