FIP200 Claw Domain Binding to p62 Promotes Autophagosome Formation at Ubiquitin Condensates

Summary

The autophagy cargo receptor p62 facilitates the condensation of misfolded, ubiquitin-positive proteins and their degradation by autophagy, but the molecular mechanism of p62 signaling to the core autophagy machinery is unclear. Here, we show that disordered residues 326–380 of p62 directly interact with the C-terminal region (CTR) of FIP200. Crystal structure determination shows that the FIP200 CTR contains a dimeric globular domain that we designated the “Claw” for its shape. The interaction of p62 with FIP200 is mediated by a positively charged pocket in the Claw, enhanced by p62 phosphorylation, mutually exclusive with the binding of p62 to LC3B, and it promotes degradation of ubiquitinated cargo by autophagy. Furthermore, the recruitment of the FIP200 CTR slows the phase separation of ubiquitinated proteins by p62 in a reconstituted system. Our data provide the molecular basis for a crosstalk between cargo condensation and autophagosome formation.

Graphical Abstract

Highlights

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  p62 directly interacts with the FIP200 C-terminal domain

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  Structural studies reveal a claw shape of the conserved FIP200 C-terminal domain

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  p62-ubiquitin condensates recruit FIP200 via the Claw to promote their degradation

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  LC3B outcompetes FIP200 from p62, suggesting an inbuild directionality in the system

Abstract

Turco et al. show that p62 interacts with the claw-shaped C-terminal domain of FIP200. This interaction is enhanced by p62 phosphorylation, mutually exclusive with the binding of p62 to LC3B, and promotes degradation of ubiquitinated cargo by autophagy. The recruitment of the FIP200 Claw slows the formation of p62-ubiquitin condensates in a reconstituted system.