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

Valentina Sora,Elena Papaleo,Mukesh Kumar,Emiliano Maiani,Matteo Tiberti,Matteo Lambrughi

doi:10.3389/fcell.2020.00420

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.

Highlights

Autophagy, a lysosomal self-eating process, is a conserved mechanism to maintain cellular homeostasis by recycling cellular components in response to nutrient shortage and by removing dysfunctional organelles and proteins in eukaryotic cells (Parzych and Klionsky, 2013; Bento et al, 2016; Mercer et al, 2018)
ATG8 proteins have a central role in selective autophagy, as they recognize and bind different autophagy receptors and adaptors containing a specific class of short-linear motifs (SLiMs), see section “The Interaction Between Human ATG8 Proteins and Their Biological Partners Through Short Linear Motifs, i.e., the LC3 Interacting Regions (LIRs).”
FYVE and coiled-coil domain-containing protein 1 (FYCO1) binds to all the ATG8 human orthologs (Pankiv et al, 2010; Olsvik et al, 2015), but shows a preference for LC3A and LC3B (Olsvik et al, 2015; Cheng X. et al, 2016; Atkinson et al, 2019), partially due to a specific interaction formed between D1285 at position X6 of the LIR motif and H57 in the ATG8 protein (Olsvik et al, 2015)

Summary

Introduction

A lysosomal self-eating process, is a conserved mechanism to maintain cellular homeostasis by recycling cellular components in response to nutrient shortage and by removing dysfunctional organelles and proteins in eukaryotic cells (Parzych and Klionsky, 2013; Bento et al, 2016; Mercer et al, 2018). The residues at the N- or C-terminal regions of the LIR core motif can interact with ATG8 proteins in different ways, contributing to stabilize the binding or providing specificity toward a certain class of ATG8 proteins.

Results

Conclusion