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

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.

Authors:
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Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1547657
Alternate Identifier(s):
OSTI ID: 1623701
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Published Article
Journal Name:
Molecular Cell
Additional Journal Information:
Journal Name: Molecular Cell Journal Volume: 74 Journal Issue: 2; Journal ID: ISSN 1097-2765
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
Biochemistry & Molecular Biology; Cell Biology; selective autophagy; phase separation; ubiquitin; X-ray crystallography; biochemistry; cell biology; ATG8; quality control

Citation Formats

Turco, Eleonora, Witt, Marie, Abert, Christine, Bock-Bierbaum, Tobias, Su, Ming-Yuan, Trapannone, Riccardo, Sztacho, Martin, Danieli, Alberto, Shi, Xiaoshan, Zaffagnini, Gabriele, Gamper, Annamaria, Schuschnig, Martina, Fracchiolla, Dorotea, Bernklau, Daniel, Romanov, Julia, Hartl, Markus, Hurley, James H., Daumke, Oliver, and Martens, Sascha. FIP200 Claw Domain Binding to p62 Promotes Autophagosome Formation at Ubiquitin Condensates. United States: N. p., 2019. Web. doi:10.1016/j.molcel.2019.01.035.
Turco, Eleonora, Witt, Marie, Abert, Christine, Bock-Bierbaum, Tobias, Su, Ming-Yuan, Trapannone, Riccardo, Sztacho, Martin, Danieli, Alberto, Shi, Xiaoshan, Zaffagnini, Gabriele, Gamper, Annamaria, Schuschnig, Martina, Fracchiolla, Dorotea, Bernklau, Daniel, Romanov, Julia, Hartl, Markus, Hurley, James H., Daumke, Oliver, & Martens, Sascha. FIP200 Claw Domain Binding to p62 Promotes Autophagosome Formation at Ubiquitin Condensates. United States. doi:10.1016/j.molcel.2019.01.035.
Turco, Eleonora, Witt, Marie, Abert, Christine, Bock-Bierbaum, Tobias, Su, Ming-Yuan, Trapannone, Riccardo, Sztacho, Martin, Danieli, Alberto, Shi, Xiaoshan, Zaffagnini, Gabriele, Gamper, Annamaria, Schuschnig, Martina, Fracchiolla, Dorotea, Bernklau, Daniel, Romanov, Julia, Hartl, Markus, Hurley, James H., Daumke, Oliver, and Martens, Sascha. Mon . "FIP200 Claw Domain Binding to p62 Promotes Autophagosome Formation at Ubiquitin Condensates". United States. doi:10.1016/j.molcel.2019.01.035.
@article{osti_1547657,
title = {FIP200 Claw Domain Binding to p62 Promotes Autophagosome Formation at Ubiquitin Condensates},
author = {Turco, Eleonora and Witt, Marie and Abert, Christine and Bock-Bierbaum, Tobias and Su, Ming-Yuan and Trapannone, Riccardo and Sztacho, Martin and Danieli, Alberto and Shi, Xiaoshan and Zaffagnini, Gabriele and Gamper, Annamaria and Schuschnig, Martina and Fracchiolla, Dorotea and Bernklau, Daniel and Romanov, Julia and Hartl, Markus and Hurley, James H. and Daumke, Oliver and Martens, Sascha},
abstractNote = {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.},
doi = {10.1016/j.molcel.2019.01.035},
journal = {Molecular Cell},
number = 2,
volume = 74,
place = {United States},
year = {2019},
month = {4}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1016/j.molcel.2019.01.035

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Cited by: 37 works
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