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Keynote Session II: Spontaneous Modifications in Long-Lived Proteins: Structural and Biological Implications

Date
September 15, 2020
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The focus of this Symposium is the practical application of mass spectrometry (MS) in the biotechnology industry. Mass Spectrometry is a critical analytical technology used in the discovery, development, and commercialization of biopharmaceuticals…

Long-lived proteins such as alpha-synuclein, A-beta, and tau are subject to a variety of spontaneous chemical modifications. These modifications accumulate over time without the need for enzymatic catalysis. Isomerization at specific amino acid residues, including aspartic acid and serine, represents one of the more abundant spontaneous chemical modifications and one of the least studied and most difficult to detect. Indeed, traditional proteomics experiments are completely blind to such sites of isomerization. We demonstrate that isomerized residues significantly perturb proteolysis by cathepsins. In fact, residual peptide fragments of 3-4 amino acids persist even after treatment with both endo- and exopeptidases. The rates of degradation are also significantly slowed, in addition to reduced cleavage sites. We further show that isomerization takes place on a timescale of weeks, significantly increasing the pool of potentially contributing proteins. The residual fragments, which still include an unnatural amino acid, are unlikely to be suitable substrates for transporter recognition and release from the lysosome. These observations provide the foundation for a novel class of substrate-induced lysosomal malfunction that may be related to lysosomal storage associated with many age-related disorders.

Speakers

Speaker Image for Ryan Julian
University of California, Riverside

Chair


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Thumbnail for Keynote Session II: Spontaneous Modifications in Long-Lived Proteins: Structural and Biological Implications
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Long-lived proteins such as alpha-synuclein, A-beta, and tau are subject to a variety of spontaneous chemical modifications. These modifications accumulate over time without the need for enzymatic catalysis…