Journal Article

Molecular determinants regulating selective binding of autophagy adapters and receptors to ATG8 proteins

O’Reilly, Nicola, Zhang, Wenxin, Wirth, Martina, Nyoni, Lynet, Mouilleron, Stéphane, Joshi, Dhira, Razi, Minoo, Tooze, Sharon A., Johansen, Terje

2019

Overview

Autophagy is an essential recycling and quality control pathway. Mammalian ATG8 proteins drive autophagosome formation and selective removal of protein aggregates and organelles by recruiting autophagy receptors and adaptors that contain a LC3-interacting region (LIR) motif. LIR motifs can be highly selective for ATG8 subfamily proteins (LC3s/GABARAPs), however the molecular determinants regulating these selective interactions remain elusive. Here we show that residues within the core LIR motif and adjacent C-terminal region as well as ATG8 subfamily-specific residues in the LIR docking site are critical for binding of receptors and adaptors to GABARAPs. Moreover, rendering GABARAP more LC3B-like impairs autophagy receptor degradation. Modulating LIR binding specificity of the centriolar satellite protein PCM1, implicated in autophagy and centrosomal function, alters its dynamics in cells. Our data provides new mechanistic insight into how selective binding of LIR motifs to GABARAPs is achieved, and elucidate the overlapping and distinct functions of ATG8 subfamily proteins. Autophagy adaptors and receptors contain LC3-interacting region (LIR) motifs that bind selectively to the LIR docking site of GABARAP and other members of the ATG8 family. Here the authors show that in addition to the LIR motif also the region C-terminal of it is important for the binding specificity of both the centriolar satellite protein PCM1 and the ULK1 complex to GABARAP subfamily proteins.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/109 / 13/51 / 14/19 / 14/35 / 38/70 / 38/77 / 631/45/535/1266 / 631/80/39 / 82/16 / 82/83 / Adapters / Adaptor proteins / Amino Acid Motifs - physiology / Autoantigens - isolation & purification / Autoantigens - metabolism / Autophagy / Autophagy-Related Protein 8 Family - genetics / Autophagy-Related Protein 8 Family - isolation & purification / Autophagy-Related Protein 8 Family - metabolism / Autophagy-Related Protein-1 Homolog - isolation & purification / Autophagy-Related Protein-1 Homolog - metabolism / Cell Cycle Proteins - isolation & purification / Cell Cycle Proteins - metabolism / Centrioles - metabolism / Determinants / Docking / GABARAP protein / Gene Knockout Techniques / HEK293 Cells / HeLa Cells / Humanities and Social Sciences / Humans / Intracellular Signaling Peptides and Proteins - isolation & purification / Intracellular Signaling Peptides and Proteins - metabolism / multidisciplinary / Nuclear Proteins - isolation & purification / Nuclear Proteins - metabolism / Organelles / Phagocytosis / Protein Binding - physiology / Proteins / Proteolysis / Quality control / Receptors / Recombinant Proteins - genetics / Recombinant Proteins - isolation & purification / Recombinant Proteins - metabolism / Residues / Science / Science (multidisciplinary) / Selective binding