Protein Motifs: Zinc Fingers

Sandra Meyer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, France
Bruno Kieffer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, France

Published online: March 2015

DOI: 10.1002/9780470015902.a0020395

Abstract

Zinc is a catalytic, structural and regulatory ion involved in a wide variety of biological processes. It is essential for stabilising the fold of biomolecules called ‘zinc finger’, a term that originates from the finding of the particular organisation of zinc coordinating amino‐acids in the primary sequence of the TFIIIA transcription factor. Zinc fingers currently designate a vast family of protein domains and folds found in proteins involved in both protein–nucleic acids and protein–protein interactions. The variety of folds stabilised by zinc as well as genome sequence analysis suggests that zinc has played an important role in the evolution of the proteome. The modular structure of zinc fingers allowed the design of very specific DNA‐ and RNA‐binding proteins opening a wide range of applications such as artificial nucleases or transcription factors.

Key Concepts

  • Zinc fingers are small folded protein domains, involved in numerous biological processes.
  • Zinc coordination by proteins allowed the evolution of a wide variety of folds.
  • Zinc ions have a wide range of affinities for proteins zinc‐binding sites, allowing metal exchange.
  • Zinc fingers are involved in protein–protein and protein–DNA interactions.
  • The rules underlying the specific recognition of DNA sequences by C2H2 zinc fingers are known, enabling the design of artificial DNA enzymes.

Keywords: zinc finger; protein evolution; protein/nucleic acid or protein interactions; protein domains

Figure 1. Evolution of the number of zinc‐finger three‐dimensional structures in the Protein Data Bank, since the first structure of the NCp7 zinc knuckle was released in 1989. The number of structures determined in solution by nuclear magnetic resonance is shown in blue while those determined from X‐ray diffraction are shown in red. Over the past years, the larger proportion of the later results from the increasing size of zinc‐finger‐containing macromolecular complexes whose structure is mostly determined by X‐ray crystallography. This trend is depicted by few examples of structures shown as ribbon diagram ranging from (a) before 1989, the original drawing of a zinc finger of TFIIIA, (b) 1990: the solution structure of the NCp7 zinc knuckle (pdb: 2ZNF), (c) 1996: the crystal structure of three C2H2 zinc fingers from ZIF268 in complex with a 11‐bp double stranded DNA oligonucleotide (pdb: 1FAAY) and (d) 2011: the crystal structure of the P300 TAZ2 domain bound to MEF2 on DNA (pdb: 3p57). The structural statistics are based on the PROSITE database 20.107 (2014).
Figure 2. High‐resolution crystal structure of the Plant HomeoDomain (PHD) finger within the RAG2 (Recombination Activating Gene 2). This domain recognises tri‐methylated lysines from the histone H3. The side chains of the histidine and cysteine residues involved in the zinc coordination sphere are shown. The numbering of the zinc coordinating residues highlights the cross‐brace organisation of these residues in the protein sequence that characterises PHD fingers. The coordination site ZN2 displays interesting features that are usually found in ZnF. Histidine residues coordinate zinc ions either via its Nδ1 or via its Nϵ2 side chain atoms. The zinc coordination sphere is stabilised by backbone‐side‐chain hydrogen bonds such as between backbone amide and the sulphur atom of the cysteine. The structure was solved with a resolution of 1.1 Å (pdb: 2 V89).
Figure 3. Tandem array of C2H2 ZnFs can be used to achieve highly specific DNA sequence recognition, a feature that is used to design artificial nucleases (Gaj , ). Two proteins are engineered, each containing three ZnFs fused to a non‐specific endonuclease domain. ZnFs recognise DNA through specific interactions between amino acids located at the C‐terminal end of their alpha‐helices and DNA bases of both strands. The co‐localisation of two nuclease domains on the DNA leads to their dimerisation and subsequently to DNA cleavage. Higher specificity can be obtained by extending the number of ZnFs.
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Gamsjeager R , Liew CK , Loughlin FE , Crossley M and Mackay JP (2007) Sticky fingers: zinc‐fingers as protein‐recognition motifs. Trends in Biochemical Sciences 32: 63–70.

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Related Sub-Topics:

Protein Folding, Evolution and Degradation | Proteins: Structure, Function, Metabolism | Protein Structure | Biomolecular Interactions
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Article Title: Protein Motifs: Zinc Fingers
 
How to Cite close
Meyer, Sandra, and Kieffer, Bruno(Mar 2015) Protein Motifs: Zinc Fingers. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020395]