Molecular effects of cancer-associated somatic mutations on the structural and target recognition properties of Keap1

Kelch-like ECH-associated protein 1 (Keap1) plays an important regulatory role in the Nrf2-dependent oxidative stress response pathway. It functions as a repressor of Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor that initiates the expression of cytoprotective enzymes during oxidative stress to protect cells from damage caused by reactive oxygen species. Recent studies show that mutations of Keap1 can lead to aberrant activation of the antioxidant pathway, which is associated with different types of cancers. To gain a mechanistic understanding of the links between Keap1 mutations and cancer pathogenesis, we have investigated the molecular effects of a series of mutations (G333C, G350S, G364C, G379D, R413L, R415G, A427V, G430C, and G476R) on the structural and target recognition properties of Keap1 by using nuclear magnetic resonance spectroscopy, circular dichroism, and isothermal titration calorimetry. Depending on their locations in the protein, these mutations are found to exert differential effects on the protein stability and target binding. Together with the proposed Hinge-and-Latch mechanism of Nrf2/Keap1 binding in literature, our results provide important insight into the molecular impact of different somatic mutations on Keap1’s function as a Nrf2 repressor.
Source: BJ Disease - Category: Biochemistry Authors: Tags: BJ Biomolecules Source Type: research