Characterization of BACE2 substrate specificity by determining its preferred peptide substrate sequences

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Characterization of BACE2 substrate specificity by determining its preferred peptide substrate sequences

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2016-12

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Proteases play critical roles in a variety of vital biological processes including the regulation, breakdown, and recycling of proteins. Understanding the preferred amino acid sequence for a given protease can elucidate its substrates and therefore its function. The information from this characterization can be used to develop inhibitors of a protease to treat disease or to suggest potential undesired effects resulting from its inhibition. The β-secretase membrane-associated aspartyl protease family consists of two homologs, BACE1 and BACE2. BACE1 has been studied in depth as the primary member of this family leading to Alzheimer’s disease (AD) while its homolog BACE2 has been largely ignored because BACE2 mRNA is minimally expressed in the brain and was originally thought to be minimally involved in AD. However, BACE2 is expressed in a number of human organs including the brain where its physiological functions remain largely unknown. Characterization of the substrate cleavage sequence preference of BACE2 should help not only to identify putative substrates and its native and AD-related functions, but also may influence AD drug development. Proteomic identification of cleavage sites (PICS) is a combined proteomic and mass spectrometric method for characterizing the cleavage site preferences of proteases. It is less biased than previous methods requiring the synthesis of a small number of peptides designed around a specific amino acid sequence. Briefly, peptide fragments generated by the BACE2 cleavage of semi-random peptide libraries are sequenced by mass spectrometry. The remaining portion of recognition and cleavage sequence is determined using bioinformatics and database searching. With the preferred sequence(s) determined, we will then search the human proteome for novel putative substrates of BACE2. In summary, a first step towards a better understanding of BACE2 is to analyze its substrate specificity and then use that information to identify its native substrates which will enable us to elucidate its native and AD-related functions.

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University of Minnesota M.S. thesis. December 2016. Major: Chemistry. Advisor: Joseph Johnson. 1 computer file (PDF); viii, 38 pages.

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Kim, Hyojung. (2016). Characterization of BACE2 substrate specificity by determining its preferred peptide substrate sequences. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/202084.

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