Molecular interactions and functional organization of Golgi glycosyltransferases acting on N-glycans.

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

F101, Aapistie 7C, University of Oulu

Topic of the dissertation

Molecular interactions and functional organization of Golgi glycosyltransferases acting on N-glycans.

Doctoral candidate

Master of Science Fawzi Khoder-Agha

Faculty and unit

University of Oulu Graduate School, Faculty of Biochemistry and Molecular Medicine, Glycan biosynthesis

Subject of study

Biochemistry and molecular medicine

Opponent

Professor Rita Gerardy-Schahn , Hannover Medical School, Germany

Custos

Docent Sakari Kellokumpu, University of Oulu

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Glycosyltransferase-enzymes' complex organisation regulates glycan synthesis in the Golgi

The structure-function relatedness of biomolecules, such as DNA, RNA and proteins, in living organisms has been extensively studied; however, such knowledge remains vastly incomplete without investigating and appreciating the contribution of glycans in molecular communications.

Glycans are branches of sugar molecules (carbohydrates) covalently attached to proteins and lipids. They mediate cell-cell interactions, cell-molecule interactions and protein-protein interactions, and are essential for the development, protection and healthy functioning of an organism. In contrast to the nucleic acid and protein synthesis, where information flows based on templates, glycans are synthesized in a matrix-free process, and are rapidly and constantly modified depending on the cell type and the cellular state. These sugar modifications form a flexible code, termed the glyco-code, and are necessary for cellular adaptation and survival. The resulting glycan structures are mediated by the dynamic interplay between sugar-adding enzymes called glycosyltransferases, sugar-removing enzymes called glycosidases and sugar pumps or transporters called nucleotide sugar transporters. The sugar branching begins in the endoplasmic reticulum and is finalized in the Golgi apparatus. Afterwards, the glycosylated proteins and lipids are transported to their final destination.

In this thesis, the molecular drivers and environmental factors behind the cooperation between glycosyltransferases themselves and between glycosyltransferases and nucleotide sugar transporters were investigated in live cells and in vitro using an array of biochemical, biophysical and microscopy techniques.

These studies reveal that glycosyltransferases’ interactions are sensitive to physiological changes in the cell, and that along with nucleotide sugar transporters, they form functional heteromeric complexes and sub-complexes. In this thesis the function of these assemblies is suggested to be the regulation and activation of their members and the efficient channeling of the substrate for fast and sequential glycan synthesis. Hence, changes in the homeostasis of diseased cells destabilize these complexes and lead to abnormal glycan structures. The detailed organizational pattern described in this thesis is shown to be responsible for the glycome flexibility and heterogeneity. Such complexes determine the glycan outcome and consequently drive the cellular adaptation to stimulus.

Altogether, the knowledge gained from these studies makes a strong and significant contribution to the field of glycobiology and opens new venues in understanding glycan modifications in health and disease.
Last updated: 12.9.2019