Zinc Fingers

By Jennifer McDowall

Protein-protein and protein-nucleic acid interactions are essential functions of many proteins. Proteins have developed different ways to bind other molecules. Zinc-binding repeats, known as zinc fingers (ZnF), are one such molecular scaffold. First identified as a zinc-binding domain responsible for binding DNA in the transcription factor IIIA from Xenopus oocytes, there are now multiple superfamilies of ZnF proteins known to bind DNA, RNA or protein. In addition, there are various classes of synthetically produced ZnF proteins that target specific genomic sites. These different ZnF proteins display versatility in both structure and function.

Zinc Finger Motifs

Several different ZnF motifs have been characterised, and vary with regard to structure, as well as binding modes and affinities. ZnF motifs can coordinate one or more zinc atoms. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that ZnF motifs are stable scaffolds that have evolved specialised functions. Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target. Most ZnF proteins contain multiple finger-like protrusions that make tandem contacts with their target molecule, often recognising extended substrates. A few of the most common structurally defined ZnF motifs are described below.

Classical (C2H2) ZnF motifs

These motifs contain a short beta hairpin and an alpha helix (beta/beta/alpha structure), where a single zinc atom is held in place by Cys(2)His(2) (C2H2), Cys(2)HisCys (C2HC), or Cys(3)His (CCCH) residues. These are the most common DNA-binding motifs found in eukaryotic transcription factors. Transcription factors usually contain several zinc fingers (each with a conserved beta/beta/alpha structure) capable of making multiple contacts along the DNA.

GATA-type ZnF motifs

These motifs constitute type IV ZnFs with the general sequence C-X(2)-C-X(17-20)-C-X(2)-C, followed by a highly basic region. They can be subdivided into subgroups depending upon the length of the internal loop: type IVa have a 17-residue loop (CX2CX17CX2C), while type IVb have a 18-residue loop (CX2CX18CX2C). ZnF motifs with 19 or 20-residue loops are rare and found mainly in fungi. GATA factors play essential roles in development, differentiation and control of cell growth in eukaryotes. GATA proteins often contain more than one ZnF domain, where one domain binds DNA and the other modulates DNA binding, often by binding other factors.

RanBP-type ZnF motifs

These motifs consist of two short beta hairpins that sandwich a single zinc atom, and are similar in structure to the zinc-ribbon fold. These domains were first identified in the nuclear export protein RanBP2. RanBP ZnF domains are known to interact with ubiquitin.

A20-type ZnF motifs

These motifs bind a single zinc atom and were first identified in protein A20. These motifs are known to bind to ubiquitin, but contact a different region of ubiquitin from RanBP ZnF motifs.

LIM-type ZnF motifs

LIM domains coordinate one or more zinc atoms, and are named after the three proteins (LIN-11, Isl1 and MEC-3) in which they were first found. They consist of two zinc-binding motifs that resemble GATA-like ZnFs, however the residues holding the zinc atom(s) are variable, involving Cys, His, Asp or Glu residues. LIM domains are involved in proteins with differing functions, including gene expression, and cytoskeleton organisation and development. Protein containing LIM ZnF domains include the adaptor protein PINCH.

MYND-type ZnF motifs

MYND domains coordinate two zinc atoms, and are named after the three proteins (Myeloid translocation protein 8, Nervy, and DEAF-1) in which they were first found. They consist of two zinc-binding motifs, the first containing a short beta-hairpin, while the second consists of two short alpha-helices. Proteins containing MYND ZnF domains include the transcriptional co-repressor protein BS69.

RING-type ZnF motifs

RING (really interesting new gene) domains coordinate two zinc atoms. Protein containing RING ZnF domains include KAP-1, PML, and several E3 ubiquitin ligases (catalyse final step of protein ubiquitination pathway).

PHD-type ZnF motifs

PHD domains coordinate two zinc atoms, and are named after the class of proteins (plant homeodomain) in which they were first found. PHD ZnF domains differ from RING-type domains in containing a highly conserved Trp residue involved in the hydrophobic core; this residue is exposed to solvent in RING-type ZnF domains. Protein containing PHD ZnF domains include Ing2 (inhibitor of growth protein 2), BPTF, Pygopus (Wnt signalling pathway), WSTF transcription factor, and Datf1 (Death-associated transcription factor 1).

TAZ-type ZnF motifs

TAZ (transcriptional adaptor zinc-binding) domains consist of two ZnF motifs form a distinct fold unrelated to other ZnFs. Protein containing TAZ ZnF domains include CBP acetyltranscferase.

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