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FIP200 claw domain binding to p62 promotes autophagosome formation at ubiquitin condensates

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Item Type:Article
Title:FIP200 claw domain binding to p62 promotes autophagosome formation at ubiquitin condensates
Creators Name:Turco, E. and Witt, M. and Abert, C. and Bock-Bierbaum, T. and Su, M.Y. and Trapannone, R. and Sztacho, M. and Danieli, A. and Shi, X. and Zaffagnini, G. and Gamper, A. and Schuschnig, M. and Fracchiolla, D. and Bernklau, D. and Romanov, J. and Hartl, M. and Hurley, J.H. and Daumke, O. and Martens, S.
Abstract: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.
Keywords:Selective Autophagy, Phase Separation, Ubiquitin, X-Ray Crystallography, Biochemistry, Cell Biology, ATG8, Quality Control
Source:Molecular Cell
ISSN:1097-2765
Publisher:Cell Press (U.S.A.)
Volume:74
Number:2
Page Range:330-346
Date:18 April 2019
Official Publication:https://doi.org/10.1016/j.molcel.2019.01.035
PubMed:View item in PubMed

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