N-glycosylation of enhanced aromatic sequons to increase glycoprotein stability |
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Authors: | Price Joshua L Culyba Elizabeth K Chen Wentao Murray Amber N Hanson Sarah R Wong Chi-Huey Powers Evan T Kelly Jeffery W |
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Institution: | Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA. |
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Abstract: | N-glycosylation can increase the rate of protein folding, enhance thermodynamic stability, and slow protein unfolding; however, the molecular basis for these effects is incompletely understood. Without clear engineering guidelines, attempts to use N-glycosylation as an approach for stabilizing proteins have resulted in unpredictable energetic consequences. Here, we review the recent development of three "enhanced aromatic sequons," which appear to facilitate stabilizing native-state interactions between Phe, Asn-GlcNAc and Thr when placed in an appropriate reverse turn context. It has proven to be straightforward to engineer a stabilizing enhanced aromatic sequon into glycosylation-na?ve proteins that have not evolved to optimize specific protein-carbohydrate interactions. Incorporating these enhanced aromatic sequons into appropriate reverse turn types within proteins should enhance the well-known pharmacokinetic benefits of N-glycosylation-based stabilization by lowering the population of protease-susceptible unfolded and aggregation-prone misfolded states, thereby making such proteins more useful in research and pharmaceutical applications. |
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