3WDZ

Crystal Structure of Keap1 in Complex with phosphorylated p62

Summary for 3WDZ

• Entry DOI: 10.2210/pdb3wdz/pdb
• Related: 1X2J 3ADE
• Descriptor: Kelch-like ECH-associated protein 1, Peptide from Sequestosome-1 (3 entities in total)
• Functional Keywords: kelch repeat, transcription, p62, nucleus
• Biological source: Mus musculus (mouse); More
• Cellular location: Cytoplasm: Q9Z2X8 Q64337
• Total number of polymer chains: 2
• Total formula weight: 35881.73

Authors

Fukutomi, T.,Takagi, K.,Mizushima, T.,Tanaka, K.,Komatsu, M.,Yamamoto, M. (deposition date: 2013-06-26, release date: 2013-09-04, Last modification date: 2024-11-13)

Primary citation

Ichimura, Y.,Waguri, S.,Sou, Y.S.,Kageyama, S.,Hasegawa, J.,Ishimura, R.,Saito, T.,Yang, Y.,Kouno, T.,Fukutomi, T.,Hoshii, T.,Hirao, A.,Takagi, K.,Mizushima, T.,Motohashi, H.,Lee, M.S.,Yoshimori, T.,Tanaka, K.,Yamamoto, M.,Komatsu, M.
Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy.
Mol.Cell, 51:618-631, 2013

PubMed Abstract: The Keap1-Nrf2 system and autophagy are both involved in the oxidative-stress response, metabolic pathways, and innate immunity, and dysregulation of these processes is associated with pathogenic processes. However, the interplay between these two pathways remains largely unknown. Here, we show that phosphorylation of the autophagy-adaptor protein p62 markedly increases p62's binding affinity for Keap1, an adaptor of the Cul3-ubiquitin E3 ligase complex responsible for degrading Nrf2. Thus, p62 phosphorylation induces expression of cytoprotective Nrf2 targets. p62 is assembled on selective autophagic cargos such as ubiquitinated organelles and subsequently phosphorylated in an mTORC1-dependent manner, implying coupling of the Keap1-Nrf2 system to autophagy. Furthermore, persistent activation of Nrf2 through accumulation of phosphorylated p62 contributes to the growth of human hepatocellular carcinomas (HCCs). These results demonstrate that selective autophagy and the Keap1-Nrf2 pathway are interdependent, and that inhibitors of the interaction between phosphorylated p62 and Keap1 have potential as therapeutic agents against human HCC.

PubMed: 24011591
DOI: 10.1016/j.molcel.2013.08.003

Experimental method

X-RAY DIFFRACTION (2.6 Å)