Potential Role of Forbidden Disulfides in Zn Signalling

Abstract

Expulsion of Zn2+ from proteins following oxidation of ligating Cysteine residues is an emerging area of the oxidative stress response. During a recent data mining survey of protein structures with pairs of thiols in both reduced and oxidized (disulfide bonded) states, we found two structural motifs repeatedly associated with Zn2+ binding (1). Forbidden disulfides are a canonical set of disulfides with abnormal stereochemistry associated with redox-activity. Here we show through systematic analysis of Zinc finger structures and sequences, that one of these motifs is extremely prevalent in Zinc fingers. We show that in around 50% of Zinc finger structures two of the Zn2+-ligating thiols are embedded in a secondary structure similar to an anti-parallel β-diagonal disulfide-like motif (aBDD), located on the β-hairpin structure known as a Zinc knuckle. Formation of a disulfide by thiols of this motif has recently been characterized in the molecular chaperone Hsp33 and also demonstrated in several other transcription factors (2). Although other forbidden disulfide motifs are occasionally present in Zinc fingers, none are as ubiquitous as this aBDD-like motif. We show that the presence of this motif and its position in the structure is characteristic of different types of Zinc fingers, suggesting a functional relationship. As Zinc fingers comprise more than 17% of the human genome, this motif is likely important in Zn2+ signalling.1. Fan SW, George RA, Haworth NL, Feng LL, Liu JY, Wouters MA. Conformational changes in redox pairs of protein structures. Prot. Sci. 18: 1745–1765, 2009.2. Ilbert M, Horst J, Ahrens S, Winter J, Graf PCF, Lilie H, Jakob U. The redox-switch domain of Hsp33 functions as dual stress sensor. Nat. Struct. Mol. Biol. 14: 556–563, 2007.