Structural analysis of the complex of Keap1 with a prothymosin alpha peptide.
The Nrf2 transcription factor, which plays important roles in oxidative and xenobiotic stress, is negatively regulated by the cytoplasmic repressor Keap1. The beta-propeller/Kelch domain of Keap1, which is formed by the double-glycine repeat and C-terminal region domains (Keap1-DC), interacts directly with the Neh2 domain of Nrf2. The nuclear oncoprotein prothymosin alpha (ProTalpha) also interacts directly with Keap1 and may play a role in the dissociation of the Keap1-Nrf2 complex. The structure of Keap1-DC complexed with a ProTalpha peptide (amino acids 39-54) has been determined at 1.9 A resolution. The Keap1-bound ProTalpha peptide possesses a hairpin conformation and binds to the Keap1 protein at the bottom region of the beta-propeller domain. Complex formation occurs as a consequence of their complementary electrostatic interactions. A comparison of the present structure with recently reported Keap1-DC complex structures revealed that the DLG and ETGE motifs of the Neh2 domain of Nrf2 and the ProTalpha peptide bind to Keap1 in a similar manner but with different binding potencies.
Padmanabhan
Balasundaram
B
Genomic Sciences Center, Yokohama Institute, RIKEN, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan. paddy@gsc.riken.jp
Nakamura
Yoshihiro
Y
Yokoyama
Shigeyuki
S
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011498:Protein Precursors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020539:Sequence Analysis, Protein / Q000379:methods*; D013947:Thymosin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D010446:Peptide Fragments; D011498:Protein Precursors; C040782:prothymosin alpha; D013947:Thymosin