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Structural biology of cellular autophagy

Structural biology of cellular autophagy
Besides its vital role in nutrient starvation, macroautophagy is now considered the most important cellular degradation pathway for elimination of long-lived macromolecules and surplus organelles. In this process, cargo is sequestered by double-membrane vesicles (autophagosomes), which later fuse with the lysosomal compartment. Formation of these organelles critically depends on the Atg8 family of ubiquitin-like proteins, which in mammalian cells is represented by several homologues, including GABAA receptor-associated protein (GABARAP). We were among the first to determine the three-dimensional structures of human GABARAP and yeast Atg8. We have extensively characterized the ligand binding mode of GABARAP using state-of-the-art techniques, including X-ray crystallography, NMR spectroscopy and fluorescence imaging. Recently, we were able to show that GABARAP specifically interacts with certain members of the Bcl-2 family of apoptosis regulators, thus extending the basis for coordinate regulation of stress-responsive pathways.
Our current research focuses on the structure and function of both established players and candidate regulatory molecules in the autophagy process; these include (1) LC3C, a poorly characterized member of the Atg8 family with remarkable properties, (2) Atg101, an essential component of the autophagic initiator complex in mammalian cells, and (3) the membrane-anchored immunophilin FKBP38, which modulates Bcl-2 function via a hitherto unknown mechanism.

Structural Biochemistry:
O. H. Weiergräber, A. Boeske, C. Krichel, M. Michel, J. Mohrlüder, M. Schwarten, S. Weber, D. Willbold

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