Engineered OAA lectins as selective and sensitive high mannose glycan targeting tools
Ackermann, B. E.; Hall, E.; Mariscal, V. T.; Clark, A.; Corbett, K. D.; Carlin, A.; Guseman, A.
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The Oscillatoria agardhii agglutinin (OAA) lectin interacts with N-glycans through a pentamannose core shared among all high mannose N-glycans (HMGs). Because HMGs only differ by number of mannose sugars, there is a scarcity of tools sensitive enough to resolve each specific HMG structure in their biological context. Here, we investigate the sequence space of OAA to tune the binding properties towards selectivity of Man5GlcNAc2, thus generating a structure-specific detection tool. Using phage display to screen a diverse library of OAA variants, we identify a variant with high selectivity for Man5GlcNAc2 that we further dissect to reveal four mutations necessary for selectivity and two mutations responsible for enhanced affinity for all HMGs. Coupling a crystal structure of the selective variant with binding analysis of specific point mutations, we reveal how co-dependent mutations achieve selectivity. We then demonstrate how variants can be valency-modulated on a single beta-barrel scaffold to improve their binding properties by orders of magnitude. Finally, we showcase the applicability of engineered OAA variants as improved HMG profiling tools and tunable antiviral agents.
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