Project Details
Projekt
Protein-lipid interactions and the influence of cellular lipid environments on glycosylation processes
Applicant
Professorin Dr. Britta Brügger
Subject Area
Biochemistry
Term
since 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 289991887
The addition of carbohydrate residues to acceptor molecules is a ubiquitous modification of proteins conserved across all domains of life. Glycosylation events range from the addition of monosaccharides to the attachment of highly complex carbohydrate chains to protein and lipid acceptors. The high number of possible combinations of different lengths, compositions and arrangements of the glycan chains results in an unmatched complexity of the human glycome, which is brought about by ~200 glycosyltransferases with different substrates. This enormous structural diversity is reflected in the broad range of functions that can be affected by glycosylation, including protein folding, trafficking/localisation and regulation of protein activity. Glycosylation defects such as those that occur in congenital disorders of glycosylation (CDGs) would also be expected to have a direct impact on the lipid composition of membrane domains, e.g. by perturbing the localisation of enzymes involved in lipid synthesis and signalling. In addition to its direct effects on lipid synthesis, aberrant glycosylation can also indirectly affect lipids and lipid signalling. In both cases, altered lipid homeostasis is likely to contribute to the pathophysiology of these multisystemic disorders. Here we aim to investigate the roles of lipids in modulating the assembly, activity and specificity of glycosylation enzymes. We will focus on dolichol phosphate mannose synthase, a key enzyme in N-glycosylation as well as C- and O-mannosylation. Using both in vitro and cellular approaches we will investigate contributions of membrane lipids to the structure and function of the enzyme. In addition, in collaboration with the other members of the Research Unit, we will study whether and how CGDs affect intracellular lipid homeostasis, using different eukaryotic model systems, ranging from human patient fibroblasts to mouse and fish models. Employing quantitative nano-mass spectrometry, we will study lipid pathway alterations in CDG to determine the consequences of hypoglycosylation on cellular lipid homeostasis. Taken together, we aim to elucidate the interplay between lipids and glycosylation enzymes and to determine how glycosylation defects can effect cellular and organismal lipid homeostasis.
DFG Programme
Research Units
