한빛사논문, 상위피인용논문
- 조회3,343
Hyunjoo Cha-Molstad1, Ji Eun Yu1,2, Zhiwei Feng3,4,5,6, Su Hyun Lee7, Jung Gi Kim1,8, Peng Yang3,4,5,6, Bitnara Han9, Ki Woon Sung7, Young Dong Yoo7, Joonsung Hwang1, Terry McGuire3,4,5,6, Sang Mi Shim7, Hyun Dong Song 10, Srinivasrao Ganipisetti1, Nuozhou Wang3,4,5,6, Jun Min Jang7,15, Min Jae Lee11, Seung Jun Kim12, Kyung Ho Lee1, Jin Tae Hong2, Aaron Ciechanover7,13, Inhee Mook-Jung10, Kwang Pyo Kim9, Xiang-Qun Xie3,4,5,6,*, Yong Tae Kwon7,14,* & Bo Yeon Kim1,8,*
1World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon 28116, Korea. 2Department of Drug Discovery and Development, College of Pharmacy, Chungbuk National University, Chungbuk, Cheongju 28644, Korea. 3Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15260, USA. 4NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA 15260, USA. 5Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA. 6Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA. 7 Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea. 8Department of Biomolecular Science, University of Science and Technology (UST), Daejeon 34113, South Korea. 9Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin 17104, Korea. 10Department of Biochemistry and Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. 11Department of Biochemistry and Molecular Biology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. 12Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea. 13 Technion Integrated Cancer Center (TICC), Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel. 14 Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 03080, Korea. 15Present address: QC Team Operation Part Sample Managements, Samsung Biologics, Yeonsu-gu, Incheon 21987, Korea.
Hyunjoo Cha-Molstad, Ji Eun Yu, Zhiwei Feng, Su Hyun Lee, Jung Gi Kim, and Peng Yang contributed equally to this work.
Correspondence to Xiang-Qun Xie or Yong Tae Kwon or Bo Yeon Kim
Abstract
Macroautophagy mediates the selective degradation of proteins and non-proteinaceous cellular constituents. Here, we show that the N-end rule pathway modulates macroautophagy. In this mechanism, the autophagic adapter p62/SQSTM1/Sequestosome-1 is an N-recognin that binds type-1 and type-2 N-terminal degrons (N-degrons), including arginine (Nt-Arg). Both types of N-degrons bind its ZZ domain. By employing three-dimensional modeling, we developed synthetic ligands to p62 ZZ domain. The binding of Nt-Arg and synthetic ligands to ZZ domain facilitates disulfide bond-linked aggregation of p62 and p62 interaction with LC3, leading to the delivery of p62 and its cargoes to the autophagosome. Upon binding to its ligand, p62 acts as a modulator of macroautophagy, inducing autophagosome biogenesis. Through these dual functions, cells can activate p62 and induce selective autophagy upon the accumulation of autophagic cargoes. We also propose that p62 mediates the crosstalk between the ubiquitin-proteasome system and autophagy through its binding Nt-Arg and other N-degrons.
논문정보
- Research article
- 2017년 07월 (BRIC 등록일 2017-07-28)
- 국내(교신)+국외 연구진
- 생명과학 > 분자생물학
- 60회 이상 인용된 논문 (상위피인용논문 등록일 2020-06-02)
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