Structure of Myosin VI/Tom1 complex reveals a cargo recognition mode of Myosin VI for tethering

Shichen Hu,Yingli Wang,Yaru Wang,Jianping Liu,Zixuan Zhou,Tao Fu,Ying Li,Lifeng Pan,Yujiao Guo

doi:10.1038/s41467-019-11481-6

Shichen Hu, Yingli Wang + Show 7 more

Open Access

https://doi.org/10.1038/s41467-019-11481-6

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Abstract

Myosin VI plays crucial roles in diverse cellular processes. In autophagy, Myosin VI can facilitate the maturation of autophagosomes through interactions with Tom1 and the autophagy receptors, Optineurin, NDP52 and TAX1BP1. Here, we report the high-resolution crystal structure of the C-terminal cargo-binding domain (CBD) of Myosin VI in complex with Tom1, which elucidates the mechanistic basis underpinning the specific interaction between Myosin VI and Tom1, and uncovers that the C-terminal CBD of Myosin VI adopts a unique cargo recognition mode to interact with Tom1 for tethering. Furthermore, we show that Myosin VI can serve as a bridging adaptor to simultaneously interact with Tom1 and autophagy receptors through two distinct interfaces. In all, our findings provide mechanistic insights into the interactions of Myosin VI with Tom1 and relevant autophagy receptors, and are valuable for further understanding the functions of these proteins in autophagy and the cargo recognition modes of Myosin VI.

Highlights

Myosin VI plays crucial roles in diverse cellular processes
We systematically characterize the interactions of Myosin VI with Tom1 and three autophagy receptors, NDP52, TAX1BP1, and Optineurin, and discover that the C-terminal region of Tom1 contains a conserved Myosin VI-binding motif shared by all Tom1 family members, which can interact with the C-terminal cargo-binding domain (CBD) of Myosin VI to form a stable heterodimeric complex
A previous study showed that the C-terminal uncharacterized region of Tom1 and the C-terminal globular cargo-binding domain of Myosin VI are responsible for the specific interaction between Tom1 and Myosin VI in cells12

Summary

Introduction

Myosin VI plays crucial roles in diverse cellular processes. In autophagy, Myosin VI can facilitate the maturation of autophagosomes through interactions with Tom and the autophagy receptors, Optineurin, NDP52 and TAX1BP1. Several adaptor proteins including Disabled-2 (Dab2), LMTK2, Tom, GIPC, NDP52, TAX1BP1, Optineurin as well as the ubiquitin proteins, have been implicated in the interactions with the C-terminal globular cargo-binding region of Myosin VI, endowing Myosin VI with specific subcellular localizations and functions. We demonstrate that Myosin VI may function as a tether to simultaneously interact with Tom and the autophagy receptor NDP52, TAX1BP1, or Optineurin, forming different ternary complexes for promoting autophagosome maturation. Our findings provide mechanistic insights into the interactions of Myosin VI with Tom and autophagy receptors, NDP52, TAX1BP1, and Optineurin, and provide a paradigm for understanding the monomeric cargo recognition mode of Myosin VI for tethering

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