title: Analysis of dimerization of BTB-IVR domains of Keap1 and its interaction with Cul3, by molecular modeling.
abstract: Oxidative damage has been associated with various neurodegenerative diseases including Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease, as well as non-neurodegenerative conditions such as cancer and heart disease. The Keap1-Nrf2 system plays a central role in the protection of cells against oxidative and xenobiotic stress. The Nrf2 transcription function and its degradation by the proteasomal pathway (Keap1-Nrf2-Cul3-Roc1 complex) are regulated by the cytoplasmic repressor protein, Keap1 which possesses BTB, BACK (IVR region) and Kelch domains. The BTB-BACK domains are important for Keap1 homo-dimerization as well as to interact with Cullin-3 for Nrf2 degradation. The crystal structure of the Keap1-Kelch domain is known; however, that of the BTB-BACK domains are not yet determined. We present here, through molecular modeling studies, the analysis of Keap1-BTB dimerization, and of BTB-BACK domains role in complex with Cul3. The electrostatic charge distribution at the BTB dimer interface of Keap1 is significantly different from other known BTB containing protein structures. Another intriguing feature is also observed that the non-conserved residues at the BTB-BACK-Cul3 interface region may play critical role for differentiating Cul3 recognition by Keap1 from other adaptor proteins for their specific substrates proteasomal degradation.
authors.affiliation: Department of Biophysics, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore 560029, India ; Department of Biochemistry, School of Biological Sciences, Madurai Kamaraj University, Madurai - 625021, India.
authors.forename: Nandini
authors.initials: N
authors.lastname: Chauhan
authors.forename: Lata
authors.initials: L
authors.lastname: Chaunsali
authors.forename: Prashant
authors.initials: P
authors.lastname: Deshmukh
authors.forename: Balasundaram
authors.initials: B
authors.lastname: Padmanabhan
keywords: BTB and IVR/BACK domains; Cul3; Keap1; Nrf2; molecular modeling