Zinc in transcription
المؤلف:
Peter Atkins, Tina Overton, Jonathan Rourke, Mark Weller, and Fraser Armstrong
المصدر:
Shriver and Atkins Inorganic Chemistry ,5th E
الجزء والصفحة:
ص734-735
2025-10-22
71
Zinc in transcription
Key points: Zinc fingers are protein structural features produced by coordination of Zn to specific histidine and cysteine residues; a sequence of these fingers enables the protein to recognize and bind to precise sequences of DNA base pairs and plays a crucial role in transferring information from the gene. The roles of Zn are either catalytic, which we will deal with later, or structural and regulatory. Unlike Ca and Mg, Zn forms more stable complexes with softer donors, so it is not surprising that it is usually found coordinated in proteins through histidine and cysteine residues. Typical catalytic sites (14) commonly have three permanent protein ligands and an exchangeable ligand (H2O), whereas structural Zn sites (15) are coordinated by four ‘permanent’ protein ligands. Transcription factors are proteins that recognize certain regions of DNA and control how the genetic code is interpreted as RNA. It has been known since the 1980s that many DNA-binding proteins contain repeating domains that are folded in place by the binding of Zn and form characteristic folds known as ‘zinc fingers’ (Fig. 27.9). In a typical case, one side of the finger provides two cysteine-S donors and the other side provides two histidine-N donors and folds as an α helix. Each ‘finger’ makes recognitory contacts with specific DNA bases. As shown in Fig. 27.10, the zinc fingers wrap around sequences of DNA that they are able to recognize by acting collectively. The high fidelity of transcription factors is the result of a number of such contacts being made along the DNA chain at the beginning of the sequence that is transcribed. The characteristic residue sequence for a Zn-finger motif is
–(Tyr,Phe)–X–Cys–X2–4–Cys–X3–Phe–X5–Leu–X2–His–X3–5–His-
where the amino acid X is variable. Aside from the ‘classical’ (Cys)2 (His)2 zinc finger, others have been discovered that have (Cys)3 His or (Cys)4 coordination, together with more elaborate examples having ‘Zn-thiolate clusters’, such as the so-called GAL4 transcription factor in which two Zn atoms are linked by bridging cysteine-S ligands (16). Various protein folds are produced, with faintly jocular names, such as ‘zinc knuckles’, joining an
Figure 27.9 Zinc fingers are protein folds that form a sequence able to bind to DNA. A typical finger is formed by the coordination of Zn (II) to two pairs of amino acid side chains located either side of the ‘fingertip’.
Figure 27.10 A pair of zinc fingers interacting with a section of DNA.
16 Zn2 (Cys)6
increasingly large family. Higher order Zn-thiolate clusters are found in proteins known as metallothioneins and some Zn-sensor proteins (see Section 27.16). Zinc is particularly suited for binding to proteins to hold them in a particular conformation: Zn2+ is high in the Irving–Williams series (Section 20.1) and thus forms stable complexes, particularly to S and N donors. It is also redox inactive, which is an important factor because it is crucial to avoid oxidative damage to DNA. Other examples of structural zinc include insulin and alcohol dehydrogenase. The lack of good spectroscopic probes for Zn, however, has meant that even though it is tightly bound in a protein, it is difficult to confirm its binding or deduce its coordination geometry in the absence of direct structural information from X-ray diffraction or NMR. However, some elegant measurements have exploited the ability of Co2+, which is coloured and paramagnetic, or Cd2+, which has useful NMR properties, to substitute for and report on the Zn site. These substitutions de pend on strong similarities between the metal ions: like Zn, Co2+ readily forms tetrahedral complexes, whereas Cd lies directly below Zn in the periodic table. For many Zn enzymes, it is found that the surrogate metals are as active as Zn itself (Section 27.9).
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