Structure and Dynamics in the ATG8 Family From Experimental to Computational Techniques

Abstract

Autophagy is a conserved and essential intracellular mechanism for the removal of damaged components. Since autophagy deregulation is linked to different kinds of pathologies, it is fundamental to gain knowledge on the fine molecular and structural details related to the core proteins of the autophagy machinery. Among these, the family of human ATG8 proteins plays a central role in recruiting other proteins to the different membrane structures involved in the autophagic pathway. Several experimental structures are available for the members of the ATG8 family alone or in complex with their different biological partners, including disordered regions of proteins containing a short linear motif called LC3 interacting motif. Recently, the first structural details of the interaction of ATG8 proteins with biological membranes came into light. The availability of structural data for human ATG8 proteins has been paving the way for studies on their structure-function-dynamic relationship using biomolecular simulations. Experimental and computational structural biology can help to address several outstanding questions on the mechanism of human ATG8 proteins, including their specificity toward different interactors, their association with membranes, the heterogeneity of their conformational ensemble, and their regulation by post-translational modifications. We here summarize the main results collected so far and discuss the future perspectives within the field and the knowledge gaps. Our review can serve as a roadmap for future structural and dynamics studies of the ATG8 family members in health and disease.

Cytoplasmic short linear motifs in ACE2 and integrin β 3 link SARS-CoV-2 host cell receptors to mediators of endocytosis and autophagy

“…Well-known SLiMs mediating protein-protein binding include the class I PSD-95/Dlg/ZO-1 (PDZ)–binding motif x[ST]xΦ-COO − (where x indicates any amino acid and Φ indicates a hydrophobic amino acid) that directs PDZ domain–containing proteins to the C-terminal tails of target proteins ( 24 ); the endocytic trafficking motif YxxΦ that binds to the clathrin adaptor AP2 μ2 ( 25 ); and the LC3-interacting region (LIR) motif, which mediates interaction with the autophagy-related protein 8 (ATG8) domain–containing proteins MAP1LC3s (microtubule-associated protein 1 light chain 3 isoforms, also called LC3s) and GABARAPs (γ-aminobutyric acid receptor–associated proteins) ( Fig. 1A ) ( 26 ).…”

Atg8-Family Proteins—Structural Features and Molecular Interactions in Autophagy and Beyond

“…In this review, we reanalyzed available information on the Atg8-family proteins, including their specific differences in sequences, structure and functions, carefully and extensively reviewed in the past years [4,5,11,25,[35][36][37][38]. However, the main goal of this work is to cast new light on the previously reported features of Atg8/LC3/GABARAP as well as to provide clarity on similarities vs. differences between the individual members of the subfamilies.…”

Cytoplasmic short linear motifs in ACE2 and integrin β3 link SARS-CoV-2 host cell receptors to endocytosis and autophagy

“…They may serve as binding sites and engage in dynamic proteinprotein interactions (18). Well-known binding motifs include the class I PDZ (PSD-95/Dlg/ZO-1) binding motif (x [ST]xΦ-COO-, where x indicates any amino acid and Φ indicates a hydrophobic amino acid) that directs PDZ domain containing proteins to the C-terminal tails of targets (19), the AP2 µ2 binding endocytic motif (YxxΦ) (20), and the LC3-interacting region (LIR) motif, which mediates the interaction with the ATG8 domain containing proteins MAP1LC3s and GABARAPs in the phagophore membrane (21). Hence, SLiMs on the cytosolic side of the host receptor proteins may allow the recruitment of proteins that enable and mediate receptor and concomitant virus particle internalisation.…”