The ubiquitous importance of protein glycosylation
Gordan Lauc
University of Zagreb Faculty of Pharmacy and Biochemistry, Zagreb, Croatia
The majority of all proteins are glycosylated and their glycan parts have numerous
structural, functional and regulatory roles. However, due to their structural
complexity, the absence of a direct genetic template and technological limitations,
the knowledge about glycans is lagging significantly behind the knowledge about
DNA and proteins. However, in the last several years an important progress has
been made and glycoscience is becoming an important focus of research in a
number of different fields of biology and medicine. Today we know that virtually all
interactions that take place at the cell surface are modulated by glycans and that
glycans are entry point for nearly all pathogenic organisms. In addition,
glycosylation is an important modulator of function of numerous intracellular,
membrane and secreted proteins.
The dogma that function of each protein is determined by its structure, which is
defined by the sequence of nucleotides in the corresponding gene, is complicated
by several additional levels of complexity which lay between genes and glycan parts
of glycoproteins. Genes determine structures of proteins which participate in the
process of glycan synthesis, but in addition to genetic polymorphisms, epigenetic
regulation of gene expression, posttranslational modifications and the activity of
the corresponding proteins interact to shape the final structure of a glycan. In
addition to approximately 600 known glyco-genes which participate in glycan
synthesis and recognition, there are hundreds of currently unknown genes which
regulate and coordinate this very complex process.
Recently we have completed comprehensive studies which analyzed composition
of plasma and IgG glycomes of over 5000 individuals from different European
populations. Using plasma glycome data we performed the first genome wide
association (GWA) analysis and identified several new regulatory genes, including
HNF1A which was found to be the master regulator of plasma protein fucosylation.
Subsequently we performed GWA study of the IgG glycome. The analysis of a
glycome from a single isolated protein eliminated noise from both different glycan
functions on different proteins and varying concentrations of individual protein in
plasma. Consequently, associations with genetic polymorphisms were much
stronger and enabled us to identify 9 new genes which associate with the IgG
glycome composition. The same genes were previously implicated in several
inflammatory diseases where IgG glycosylation changes were also reported;
indicating that changes in IgG glycosylation might have functional implications for
these diseases.