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Title

Analysis of dimerization of BTB-IVR domains of Keap1 and its interaction with Cul3, by molecular modeling

 

Authors

Nandini Chauhan1, 2, Lata Chaunsali1, Prashant Deshmukh1 & Balasundaram Padmanabhan1*

 

Affiliation

1Department of Biophysics, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore 560029, India; 2Department of Biochemistry, School of Biological Sciences, Madurai Kamaraj University, Madurai – 625021, India

 

Email

paddy@nimhans.kar.nic.in; *Corresponding author

 

Article Type

Hypothesis

 

Date

Received May 10, 2013; Accepted May 11, 2013; Published May 25, 2013

 

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. 

 

Keywords

Nrf2, Keap1, BTB and IVR/BACK domains, Cul3, molecular modeling.

 

Citation

Chauhan et al.  Bioinformation 9(9): 450-455 (2013)

 

Edited by

P Kangueane

 

ISSN

0973-2063

 

Publisher

Biomedical Informatics

 

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.