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 journalArticlepeer-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 languageEnglish
    Article number3291
    JournalNature communications
    Volume9
    Issue number1
    DOIs
    Publication statusPublished - 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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