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Cited by 219

The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.

Keap1, the Sensor for Electrophiles and Oxidants that Regulates the Phase 2 Response, Is a Zinc Metalloprotein

Dinkova-Kostova, Albena T., Holtzclaw, W. David, Wakabayashi, Nobunao·2005·Biochemistry
DOI 10.1021/bi047434h
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Abstract

Induction of the phase 2 response, a major cellular reaction to oxidative/electrophile stress depends on a protein triad: actin-tethered Keap1 that binds to Nrf2. Inducers react with Keap1 releasing Nrf2 for nuclear translocation and activation of the antioxidant response element (ARE), which regulates phase 2 genes. The primary sensors for inducers are certain uniquely reactive cysteine thiols of Keap1. Recombinant murine Keap1 contains 0.9 zinc atoms per monomer as determined by inductively coupled plasma-optical emission spectrometry: its zinc content depends on the metal composition of the overexpression medium. Simultaneous direct measurement of bound zinc using a pyridazoresorcinol chelator and protein thiol groups using 4,4'-dipyridyl disulfide has established that (i) zinc is bound to reactive cysteine thiols of Keap1 and is displaced stoichiometrically by inducers, (ii) with these cysteines mutated to alanine, the affinity for zinc is reduced by nearly 2 orders of magnitude, and (iii) the association constant of Keap1 for zinc is 1.02 (+/-0.19) x 10(11) M(-)(1), consistent with a Zn(2+) metalloprotein. Co(2+) substitution for Zn(2+) yields an optical spectrum consistent with tetrahedral metal coordination. Coincident binding of inducers and release of zinc alters the conformation of Keap1, as shown by a profound decline of its tryptophan fluorescence and depression of fluorescence of a hydrophobicity probe. Thus, regulation of the phase 2 response involves chemical modification of critical cysteine residues of Keap1, whose reactivity is modulated by zinc binding. Keap1 is a zinc-thiol protein endowed with a delicate switch controlled by both metal-binding and thiol reactivity.

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Metadata

Authors
Dinkova-Kostova, A. T., Holtzclaw, W. D., & Wakabayashi, N.
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
2005-04-16
Volume
44
Issue
18
Pages
6889-6899
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
DOI
10.1021/bi047434h
OpenAlex
W1966781309
Cited by
219
References
10
FWCI
5.07
Type
journal article
Language
en
Open access
closed

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