Glycation is a non-enzymatic post-translational modification (PTM) that occurs through the spontaneous attachment of aldehydes onto amino groups of proteins. While glycation is associated with several disease pathologies, it is not known how the glycation reaction occurs selectively. We are uncovering the molecular mechanisms that promote glycation based on the hypothesis that the local microenvironment, a combination of sequence and structure, is responsible for dictating the unique glycation outcome. Utilizing a top-down mass spectrometry approach, we evaluated total levels of glycation, determined distinct products, identified unique glycation sites, and correlated these data with chemical and structural features for a panel of proteins glycated <i>in vitro</i>. Our data reveal that the primary sequence dictates the overall likelihood that a site will become glycated, while the surrounding structure further sculpts the glycation outcome. Moreover, we found that the extent of glycation does not correlate with surface exposure or pKa perturbations at reactive arginines. We determined that an increase in negative charge surrounding the reactive site decreases reactivity, while polar and aromatic residues including tyrosine, stimulate glycation. Future work will further establish the positional preferences for amino acids neighboring reactive residues, and how this may alter the distribution and/or identities of the glycation adducts that form. By taking a systematic approach, we have significantly advanced the understanding of the molecular factors that govern selective glycation.

Uncovering features that control selective protein glycation

256th National Meeting (2018)

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