Insights into degradation mechanism of N-end rule substrates by p62/SQSTM1 autophagy adapter

Do Hoon Kwon; Ok Hyun Park; Leehyeon Kim; Yang Ouk Jung; Yeonkyoung Park; Hyeongseop Jeong; Jaekyung Hyun; Yoon Ki Kim; Hyun Kyu Song

doi:10.1038/s41467-018-05825-x

Insights into degradation mechanism of N-end rule substrates by p62/SQSTM1 autophagy adapter

Do Hoon Kwon, Ok Hyun Park, Leehyeon Kim, Yang Ouk Jung, Yeonkyoung Park, Hyeongseop Jeong, Jaekyung Hyun, Yoon Ki Kim, Hyun Kyu Song

Research output: Contribution to journal › Article › peer-review

62 Citations (Scopus)

Abstract

p62/SQSTM1 is the key autophagy adapter protein and the hub of multi-cellular signaling. It was recently reported that autophagy and N-end rule pathways are linked via p62. However, the exact recognition mode of degrading substrates and regulation of p62 in the autophagic pathway remain unknown. Here, we present the complex structures between the ZZ-domain of p62 and various type-1 and type-2 N-degrons. The binding mode employed in the interaction of the ZZ-domain with N-degrons differs from that employed by classic N-recognins. It was also determined that oligomerization via the PB1 domain can control functional affinity to the R-BiP substrate. Unexpectedly, we found that self-oligomerization and disassembly of p62 are pH-dependent. These findings broaden our understanding of the functional repertoire of the N-end rule pathway and provide an insight into the regulation of p62 during the autophagic pathway.

Original language	English
Article number	3291
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05825-x
Publication status	Published - 2018 Dec 1

Bibliographical note

Funding Information:
We thank the staff at beamline 5C, Pohang Accelerator Laboratory, Korea and beamline BL17A, Photon Factory, Japan for help with the X-ray data collection. This work was in part performed under the International Collaborative Research Program of Institute for Protein Research, Osaka University (ICR-17-05). Diffraction data were collected at the Osaka University beamline BL44XU at SPring-8 (Harima, Japan) (Proposal Nos. 2017A6775 and 2017B6775). We also thank the staff at beamline 4C, Pohang Accelerator Laboratory, Korea, and beamline BL10C, Photon Factory, Japan for help with the SAXS data collection. This work was supported by National Research Foundation grants from the Korean government (NRF-2016R1E1A1A01942623, BRL grant: No. 2015041919, and International Cooperation Program: No. 2015K2A2A6002008).

Publisher Copyright:
© 2018, The Author(s).

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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title = "Insights into degradation mechanism of N-end rule substrates by p62/SQSTM1 autophagy adapter",

abstract = "p62/SQSTM1 is the key autophagy adapter protein and the hub of multi-cellular signaling. It was recently reported that autophagy and N-end rule pathways are linked via p62. However, the exact recognition mode of degrading substrates and regulation of p62 in the autophagic pathway remain unknown. Here, we present the complex structures between the ZZ-domain of p62 and various type-1 and type-2 N-degrons. The binding mode employed in the interaction of the ZZ-domain with N-degrons differs from that employed by classic N-recognins. It was also determined that oligomerization via the PB1 domain can control functional affinity to the R-BiP substrate. Unexpectedly, we found that self-oligomerization and disassembly of p62 are pH-dependent. These findings broaden our understanding of the functional repertoire of the N-end rule pathway and provide an insight into the regulation of p62 during the autophagic pathway.",

author = "Kwon, {Do Hoon} and Park, {Ok Hyun} and Leehyeon Kim and Jung, {Yang Ouk} and Yeonkyoung Park and Hyeongseop Jeong and Jaekyung Hyun and Kim, {Yoon Ki} and Song, {Hyun Kyu}",

note = "Funding Information: We thank the staff at beamline 5C, Pohang Accelerator Laboratory, Korea and beamline BL17A, Photon Factory, Japan for help with the X-ray data collection. This work was in part performed under the International Collaborative Research Program of Institute for Protein Research, Osaka University (ICR-17-05). Diffraction data were collected at the Osaka University beamline BL44XU at SPring-8 (Harima, Japan) (Proposal Nos. 2017A6775 and 2017B6775). We also thank the staff at beamline 4C, Pohang Accelerator Laboratory, Korea, and beamline BL10C, Photon Factory, Japan for help with the SAXS data collection. This work was supported by National Research Foundation grants from the Korean government (NRF-2016R1E1A1A01942623, BRL grant: No. 2015041919, and International Cooperation Program: No. 2015K2A2A6002008). Publisher Copyright: {\textcopyright} 2018, The Author(s).",

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Insights into degradation mechanism of N-end rule substrates by p62/SQSTM1 autophagy adapter

Abstract

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