Structural and Dynamic Characterization of Mutated Keap1 for Varied Affinity toward Nrf2: A Molecular Dynamics Simulation Study

Journal of Chemical Information and Modeling
I-Chung ChengChia-Ning Yang

Abstract

Keap1 is an adaptor protein that regulates Nrf2 in response to oxidative stress. Under basal conditions, Nrf2 is negatively regulated through ubiquitination by Keap1. However, upon exposure to oxidative stress, the ubiquitination of Nrf2 is inhibited, resulting in an increased steady-state level of Nrf2 in the nucleus and increased transcription of cytoprotective genes. A gene variant G364C and somatic mutation G430C on Keap1 have recently been reported to substantially impair the Keap1-Nrf2 interaction and to be associated with lung cancer. By contrast, alanine scanning experiments have shown that the mutations S363A, S508A, S555A, and S602A do not affect the ability of Keap1 to bind to Nrf2, regardless of the fact that G364 and G430 are not in contact with Nrf2 whereas the four serine residues are involved in the accommodation of Nrf2 with their hydroxy groups. In this study, molecular dynamics simulations were performed to investigate the structural and dynamic variances among wild-type (WT) Keap1 and the six mutants in unbound form. Principal component analysis of the collected MD trajectories was performed to provide dynamic diversity. Our dynamic and structural observations suggest that the G364C and G430C mutants possess...Continue Reading

References

Mar 15, 2001·Proceedings of the National Academy of Sciences of the United States of America·A T Dinkova-KostovaP Talalay
Aug 24, 2002·Proceedings of the National Academy of Sciences of the United States of America·Albena T Dinkova-KostovaPaul Talalay
Nov 21, 2002·The Journal of Biological Chemistry·Daniel StewartJawed Alam
Feb 7, 2004·Proceedings of the National Academy of Sciences of the United States of America·Nobunao WakabayashiPaul Talalay
Oct 12, 2004·The Journal of Biological Chemistry·Xuchu LiLesa J Beamer
Dec 2, 2004·Molecular and Cellular Biology·Donna D ZhangMark Hannink
Mar 2, 2006·Molecular Cell·Balasundaram PadmanabhanMasayuki Yamamoto
Mar 4, 2006·The Journal of Biological Chemistry·Abhinav K Jain, Anil K Jaiswal
Oct 6, 2006·PLoS Medicine·Anju SinghShyam Biswal
Nov 4, 2006·Biological Chemistry·Kit I TongMasayuki Yamamoto
Apr 4, 2007·The Journal of Biological Chemistry·Abhinav K Jain, Anil K Jaiswal
Oct 2, 2007·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Yoriko WataiMasayuki Yamamoto
Aug 30, 2008·Chemical Research in Toxicology·Ryan HollandJames C Fishbein
Sep 2, 2008·Proceedings of the National Academy of Sciences of the United States of America·Tatsuhiro ShibataSetsuo Hirohashi
Feb 3, 2009·The Journal of Biological Chemistry·Truyen NguyenCecil B Pickett
Mar 13, 2009·The Journal of Biological Chemistry·Suryakant K Niture, Anil K Jaiswal
Aug 12, 2009·Free Radical Biology & Medicine·James W KasparAnil K Jaiswal
Aug 27, 2009·Proceedings of the National Academy of Sciences of the United States of America·Ahmet Bakan, Ivet Bahar
Sep 17, 2009·Biochemical Society Transactions·David Komander
Oct 2, 2009·Carcinogenesis·Thomas W Kensler, Nobunao Wakabayashi
Nov 26, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·James W Kaspar, Anil K Jaiswal
Dec 24, 2010·Cancer Research·Takafumi SuzukiMasayuki Yamamoto
Dec 25, 2010·Integrative Biology : Quantitative Biosciences From Nano to Macro·Chunchen LinGregory Timp
Jan 22, 2011·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Keiko TaguchiMasayuki Yamamoto
Apr 8, 2011·Bioinformatics·Ahmet BakanIvet Bahar
May 5, 2011·Nature Structural & Molecular Biology·Christian Behrends, J Wade Harper
Jul 6, 2011·Nature Reviews. Nephrology·Toshio MiyataCharles van Ypersele de Strihou
Nov 24, 2011·Free Radical Biology & Medicine·Rowena HancockGeoff Wells
May 3, 2012·Medicinal Research Reviews·Sadagopan MageshLongqin Hu
Oct 31, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Phillip Shelton, Anil K Jaiswal
Dec 29, 2012·Frontiers in Oncology·Yoichiro MitsuishiMasayuki Yamamoto
Feb 26, 2013·Free Radical Biology & Medicine·Suryakant K NitureAnil K Jaiswal

❮ Previous
Next ❯

Citations

May 19, 2016·Medicinal Research Reviews·Meng-Chen LuQi-Dong You
Nov 16, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ashwini Machhindra LondheAe Nim Pae
Mar 29, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Ibrahim Damilare BoyenleTemitope Isaac Adelusi

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.