Molecular basis for the disruption of Keap1-Nrf2 interaction via Hinge & Latch mechanism

TY - JOUR

T1 - Molecular basis for the disruption of Keap1-Nrf2 interaction via Hinge & Latch mechanism

AU - Horie, Yuta

AU - Suzuki, Takafumi

AU - Inoue, Jin

AU - Iso, Tatsuro

AU - Wells, Geoffrey

AU - Moore, Terry W.

AU - Mizushima, Tsunehiro

AU - Dinkova-Kostova, Albena T.

AU - Kasai, Takuma

AU - Kamei, Takashi

AU - Koshiba, Seizo

AU - Yamamoto, Masayuki

N1 - This work was supported in part by MEXT/JSPS KAKENHI (19H05649 to M.Y., 17K07298 to S.K., and 19K07340 and 17KK0183 to T.S.), BINDS (JP21am0101095 to M.Y.) and P-CREATE (JP20cm0106101 to M.Y.) from AMED, and Takeda Science Foundation (M.Y. and T.S.). This work was also supported in part by the Tohoku Medical Megabank Project (JP19km0105001 and JP19km0105002), Project for Promoting Public Utilization of Advanced Research Infrastructure (MEXT), and Sharing and administrative network for research equipment (MEXT).

PY - 2021/5/14

Y1 - 2021/5/14

N2 - The Keap1-Nrf2 system is central for mammalian cytoprotection against various stresses and a drug target for disease prevention and treatment. One model for the molecular mechanisms leading to Nrf2 activation is the Hinge-Latch model, where the DLGex-binding motif of Nrf2 dissociates from Keap1 as a latch, while the ETGE motif remains attached to Keap1 as a hinge. To overcome the technical difficulties in examining the binding status of the two motifs during protein-protein interaction (PPI) simultaneously, we utilized NMR spectroscopy titration experiments. Our results revealed that latch dissociation is triggered by low-molecular-weight Keap1-Nrf2 PPI inhibitors and occurs during p62-mediated Nrf2 activation, but not by electrophilic Nrf2 inducers. This study demonstrates that Keap1 utilizes a unique Hinge-Latch mechanism for Nrf2 activation upon challenge by non-electrophilic PPI-inhibiting stimuli, and provides critical insight for the pharmacological development of next-generation Nrf2 activators targeting the Keap1-Nrf2 PPI.

AB - The Keap1-Nrf2 system is central for mammalian cytoprotection against various stresses and a drug target for disease prevention and treatment. One model for the molecular mechanisms leading to Nrf2 activation is the Hinge-Latch model, where the DLGex-binding motif of Nrf2 dissociates from Keap1 as a latch, while the ETGE motif remains attached to Keap1 as a hinge. To overcome the technical difficulties in examining the binding status of the two motifs during protein-protein interaction (PPI) simultaneously, we utilized NMR spectroscopy titration experiments. Our results revealed that latch dissociation is triggered by low-molecular-weight Keap1-Nrf2 PPI inhibitors and occurs during p62-mediated Nrf2 activation, but not by electrophilic Nrf2 inducers. This study demonstrates that Keap1 utilizes a unique Hinge-Latch mechanism for Nrf2 activation upon challenge by non-electrophilic PPI-inhibiting stimuli, and provides critical insight for the pharmacological development of next-generation Nrf2 activators targeting the Keap1-Nrf2 PPI.

KW - Molecular biology

KW - Solution-state NMR

UR - https://www.scopus.com/pages/publications/85105881486

U2 - 10.1038/s42003-021-02100-6

DO - 10.1038/s42003-021-02100-6

M3 - Article

C2 - 33990683

SN - 2399-3642

VL - 4

JO - Communications Biology

JF - Communications Biology

M1 - 576

ER -