The molecular basis and functional consequences of IgG subclass glycosylation

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Carbohydrates (glycans) linked to proteins play essential roles in many aspects of life. However, their precise impacts on glycoprotein function and underlying molecular mechanisms are poorly understood, mainly due to their enormous structural variability and complexity. These features render the prediction of structure-function relationships of glycans a conceptually challenging task for which satisfying solutions have not yet been determined. Various international organizations (e.g. Euroglycoscience Forum, US National Research Council) independently recommend that substantial efforts have to be undertaken to improve our understanding of protein-carbohydrate interactions. An important prerequisite for this objective is the ability to control glycan biosynthesis. Thus glycoengineering of cells and expression hosts to achieve tight control of glycoprotein production are paramount for current and future investigations. An additional challenge in understanding the functional consequences of differential protein glycosylation especially for the human system is the fact that only a very limited number of model systems are available, allowing to place immunological/medical data within the framework of glycoscience, and vice versa. Indeed, integration of complementary scientific disciplines is mandatory to fully exploit the unique properties of protein linked glycans, and to evaluate their potential for future therapeutic approaches. By integrating the unique expertise of the group of Prof. Steinkellner in Vienna and Prof. Nimmerjahn in Erlangen, this research proposal tries to overcome these challenges. We will focus on human antibodies, which are highly variable glycoproteins and are an essential part of the immune system. By using a plant protein production system highly defined glycovariants of all human IgG subclasses will be generated which will also allow to obtain basic insights into the pathways of protein glycosylation. In addition, in vitro and novel humanized mouse model systems will be used to identify glycosylation dependent alterations in antibody activity in vivo.