4.8 Article

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

Journal

MOLECULAR CELL
Volume 74, Issue 2, Pages 330-+

Publisher

CELL PRESS
DOI: 10.1016/j.molcel.2019.01.035

Keywords

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Funding

  1. ERC [646653, 616024]
  2. Austrian Science Fund (FWF) [P30401-B21, W1261]
  3. NIH [R01 GM111730]
  4. Human Frontiers Science Program [RGP0026/2017]
  5. OEAW Doc fellowship
  6. University of California Office of the President, Multicampus Research Programs and Initiatives [MR-15-328599]
  7. National Institutes of Health [R01 GM124149, P30 GM124169]
  8. U.S. Department of Energy, Office of Basic Energy Sciences [DE-AC02-05CH11231]
  9. Austrian Science Fund (FWF) [P30401] Funding Source: Austrian Science Fund (FWF)
  10. European Research Council (ERC) [646653, 616024] Funding Source: European Research Council (ERC)

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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.

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