Keap1 (human, recombinant)

Kelch-like ECH-associated protein 1 (Keap1) is a substrate adapter protein in the Kelch-like (KLHL) family of proteins.¹ It contains an N-terminal region, a BTB/POZ domain that facilitates protein binding and Keap1 dimerization, a central intervening region (IVR), a double glycine repeat (DGR)/Kelch repeat domain, a BACK that binds to other proteins, and a C-terminal region.^1,2,3 KEAP1 is ubiquitously expressed and localized to the perinuclear region of the cytosol and bound to the actin skeleton via its DGR region.^4,5,6 Under homeostatic conditions, it associates with Nrf2, preventing its nuclear translocation and promoting its ubiquitination and proteasomal degradation.^2,6 In the presence of electrophiles or oxidants, Keap1 releases Nrf2, which translocates to the nucleus to induce the expression of cytoprotective genes.⁶ Somatic mutations in Keap1 have been found in various cancers and human cancer cell lines and are associated with loss of Keap1 function and constitutive activation of Nrf2, which contributes to tumor growth and chemoresistance.³ Cayman’s Keap1 (human, recombinant) protein is comprised of Keap1 (amino acids 2-264) fused to His and GST tags at its N-terminus, consists of 860 amino acids, and has a calculated molecular weight of 97.37 kDa. By SDS-PAGE, under reducing conditions, the apparent molecular mass of this protein is approximately 109 kDa.

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1. Dhanoa, B.S., Cogliati, T., Satish, A.G., et al. Update on the Kelch-like (KLHL) gene family. Hum. Genomics 7(1), 13 (2013).

2. Zipper, L.M., and Mulcahy, R.T. The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm. The Journal of Biological Chemisty 277(39), 36544-36552 (2002).

3. Dhamodharan, U., Ponjayanthi, B., Sireesh, D., et al. Association of single-nucleotide polymorphisms of the KEAP1 gene with the risk of various human diseases and its functional impact using in silico analysis. Pharmacol. Res. 137, 205-218 (2018).

4. Cuadrado, A., Rojo, A.I., Wells, G., et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat. Rev. Drug Discov. 18(4), 295-217 (2019).

5. Watai, Y., Kobayashi, A., Nagase, H., et al. Subcellular localization and cytoplasmic complex status of endogenous Keap1. Genes Cells 12(10), 1163-1178 (2007).

6. Kang, M.-I., Kobayashi, A., Wakabayashi, N., et al. Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proc. Natl. Acad. Sci. USA 101(7), 2046-2051 (2004).