EGFR meets hATG8s – Biophysical and structural insights supporting a unique role of GABARAP during receptor trafficking

The human ATG8 family member GABARAP is involved in numerous autophagy-related and - unrelated processes. We recently observed that specifically the deficiency of GABARAP enhances EGFR degradation upon ligand stimulation. Here, we report on two putative LC3-interacting regions (LIRs) within the EGFR, the first of which (LIR1) is selected as GABARAP binding site in-silico . Indeed, in-vitro interaction studies reveal preferential binding of LIR1 to GABARAP and GABARAPL1. Our X-ray data demonstrate interaction of core LIR1 residues FLPV with both hydrophobic pockets of GABARAP suggesting a canonical binding. Although LIR1 occupies the LIR docking site, GABARAP Y49 and L50 appear dispensable this case. Our data support the hypothesis that GABARAP affects the fate of EGFR at least in part through direct binding.