ľ¹Ï¸£ÀûÓ°ÊÓ

Summary of dissertation

This thesis investigates the amyloid-like oligomerization of Golgi-associated plant pathogenesis-related protein 1 (GAPR-1), a unique member of the CAP superfamily, and its functional role in regulating autophagy through interaction with beclin 1. The study aims to elucidate how membrane binding and oligomerization of GAPR-1 are governed by specific lipid interactions and structural determinants. A multidisciplinary approach integrating molecular dynamics simulations, biochemical assays, and yeast model systems was used to elucidate the molecular mechanisms underlying GAPR-1 function.

The findings show that GAPR-1 binds negatively charged lipids in a tilted orientation mediated by Lys7 and N-terminal myristoylation, which is essential for its subsequent oligomerization and interaction with beclin 1. Lysine residues in the N-terminal α-helix modulate the kinetics of oligomerization and biomolecular condensation. GAPR-1 binds multiple lipids through an extended interface rather than a defined pocket, with the amphipathic N-terminal α-helix likely facilitating membrane insertion and stabilization. Mutational analyses revealed that specific residues and dimer configurations regulate membrane docking, amyloid-like aggregation, and condensate dynamics. Furthermore, the study highlights the distinct regulatory roles of GAPR-1 and Bcl-2 in modulating beclin 1 activity, demonstrating that both proteins inhibit autophagy through independent but complementary pathways.

This work not only advances our understanding of how peripheral membrane proteins couple lipid binding to functional assembly, but also establishes Saccharomyces cerevisiae as a model system for studying amyloid oligomers and their functions. These insights offer implications for novel disease intervention strategies via regulation of autophagy with possibly even broader implications for targeting amyloid-related diseases, including neurodegeneration and cancer.

If a candidate gives a layman's talk, the live stream will start 15 minutes earlier.