Zinc-finger domains

The ultimate goal of protein engineering is to design an amino acid sequence that will fold into a protein with a predetermined structure and function. Paradoxically, this goal may be easier to achieve than its inverse, the solution of the folding problem. It seems to be simpler to start with a three-dimensional structure and find one of the numerous amino acid sequences that will fold into that structure than to start from an amino acid sequence and predict its three-dimensional structure. We will illustrate this by the design of a stable zinc finger domain that does not require stabilization by zinc. 

Figure 17.15 Schematic diagrams of the main-chain conformations of the second zinc finger domain of Zif 268 (red) and the designed peptide FSD-1 (blue). The zinc finger domain is stabilized by a zinc atom whereas FSD-1 is stabilized by hydrophobic interactions between the p strands and the a helix. (Adapted from B.I. Dahiyat and S.L. Mayo, Science 278 82-87, 1997.)...

Figure 2.20 Schematic representation of a zinc-finger domain from TFIIIA and related proteins. X represents any amino acid conserved amino acids are histidine (H), cysteine (C), tyrosine (Y), phenylalanine (F), and leucine (L).

Maynard, A. T., Huang, M., Rice, W. G., and Covell, D. G. 1998. Reactivity of the HIV-1 nucleocapsid protein p7 zinc finger domains from the perspective of density-functional theory. Proc. Natl. Acad. Sci. USA 95 11578-11583. 

Zinc-finger proteins are also possible targets for bicyclams. All nu-cleocapsid proteins of known strains of retroviruses contain one or two copies of an invariant sequence, Cys-X2-Cys-X4-His-X4-Cys. Proteins with this sequence bind zinc stoichiometrically with dissociation constants of ca. 10-12M (377). Under physiological conditions, a 10-fold excess of EDTA removes only 50% of zinc from the zinc finger domain of HIV-1 nucleocapsid protein (378). 

Fig. 2. Examples of the structures of protein domains and repeats. The images were generated using Molscript (Kraulis, 1991). (A) Immunoglobulin domain (PDB identifier ltlk) (Holden et al1992), (B) A zinc finger domain with coordinated zinc ion (PDB identifienlzaa) (Pavletich and Pabo, 1991). (C) A /3-propeller domain composed of seven WD40 repeats (PDB identifier lgp2) (Wall et al., 1995), (D) An elongated domain of variant leucine-rich repeats (PDB identifienllrv) (Peters et al., 1996).

Prakash, The Sacdiaromyces cerevisiae RAD 18 gene encodes a protein that contains potential zinc finger domains for nudeic acid binding and a putative nudeotide binding sequence. Nucleic Acids Res, 1988, 16(14B), 7119-31. 

D. R., and Sundquist, W. I., Structure and ubiquitin interactions of the conserved zinc finger domain of Npl4, J. Biol. Biol, 2003, 278, 20225. 

Fig. 42. The structure of the zinc finger domain of the Xenopus Xfin protein, as determined by solution NMR methods. [Courtesy of Michael Pique and Peter E. Wright, Department of Molecular Biology, Research Institute of Scripps Clinic, La Jolla, California. From Lee et al., Science 245, 635-637, 11 August 1989. Copyright 1989 by the American Association for the Advancement of Science.]...

FIGURE 7. Structure of a zinc-finger domain. Reprinted with permission from Reference 19. Copyright 2004 American Chemical Society... 

Rabphilin and RIMla/2a represent two different classes of effectors that bind to Rab3-GTP (Siidhof 2004). They have structural similarities, as both contain two C2 domains, an N-terminally located zinc-finger domain that mediates binding to GTP-Rab3, and sites for phosphorylation by PKA that are located in the center of the proteins. 

Dreier, B., Beerli, R.R., Segal, D.J., Flippin, J.D. Barbas C.F., 3rd. Development of zinc finger domains for recognition of the 5 -ANN-3 family of DNA sequences and their use in the construction of artificial transcription factors. J Biol Chem 2001 276 29466-29478. 

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