The Mammalian O‐Mannosylation Pathway: Protein Substrates and Functional Glycans

Abstract

O‐linked mannose modification imparts essential functions to targeted glycoproteins. The protein substrates, enzymes, and glycan products of the O‐mannosylation pathway underlie a variety of cellular processes and their perturbation contribute to diverse pathophysiological conditions including viral‐host interactions, tumor metastasis, axon guidance in the brain, muscle integrity, and cardiac function. Despite the broad physiologic and pathophysiologic impact of the O‐mannosylation pathway, very little is known regarding the key steps in the production of functional O‐mannose glycans. This talk focuses on identification strategies for the protein substrates for O‐mannosylation in mammalian brain and muscle, efforts to delineate the unknown enzymes in the pathway, and the assignment of the functional Omannose initiated glycan(s) structures. Towards these goals, several key tools including mass spectrometry‐based glycoanalytics, recombinant enzymes and protein expression systems, chemoenzymatic tagging methods, complex glycopeptide synthesis, and anti‐O‐glycan antibodies will be discussed. These research efforts will be highlighted that focus on providing new understanding regarding the mechanisms by which defects in the O‐mannosylation biosynthetic pathway contribute to multiple disease processes.