Trends in Biochemical Sciences
ReviewSticky fingers: zinc-fingers as protein-recognition motifs
Introduction
In the 20 years since zinc-binding repeats were first identified in a protein (TFIIIA [1]), the DNA-binding properties of zinc-fingers (ZnFs) have been explored in exquisite detail [2], and it is now even possible to generate or indeed to purchase ‘designer’ ZnF proteins that will target specific genomic sites. These TFIIIA-type or ‘classical’ ZnFs have proved to be common in complex organisms: in humans, >15 000 such domains are predicted to exist in ∼1000 different proteins [3]. More than 20 additional classes of structurally distinct modules, also termed ZnFs, have been identified [4], but it should be noted that many of these are related to classical ZnFs only by the existence of the structural zinc atom or atoms. Nevertheless, roles in nucleic acid recognition are almost invariably postulated when these domains are first described. In some cases, these predictions have been borne out: both GATA- and Gal4-type ZnFs recognize DNA in a sequence-specific manner 5, 6, and several ZnF domains can bind to RNA (reviewed in Refs 7, 8, 9, 10).
It has also emerged, however, that ZnFs can mediate protein–protein interactions [11]. In the past 3–5 years, detailed structural and functional data have been reported for several ZnF–protein interactions (Table 1), showing unequivocally that several classes of ZnFs (including classical ZnFs) can function as protein recognition motifs. Here we review the current understanding of ZnFs as protein recognition motifs with a strong emphasis on those ZnF classes for which the structural basis has been determined.
Section snippets
One-zinc wonders: classical, GATA, RanBP and A20 ZnFs
In the following sections, zinc-binding domains have been grouped according to their zinc ligation topology. We first consider domains that coordinate a single zinc atom. Several of these classes of ZnFs are well known as DNA recognition motifs and, notably, the interface used by some of these domains to contact DNA often differs from that involved in protein–protein interactions.
MYND your LIMs
Several classes of ZnFs coordinate more than one zinc atom. LIM domains (named after the three proteins, LIN-11, Isl1 and MEC-3, in which they were first discovered [43]) and MYND domains (named after the three proteins myeloid translocation protein 8, Nervy and DEAF-1 [44]) both comprise two sequential zinc-binding motifs that pack against each other to make a single compact domain. Both of these domains mediate protein–protein interactions.
Cross-brace yourself for PHD and RING action
Like LIM and MYND domains, RING (‘really interesting new gene’ [53]) and PHD (‘plant homeodomain’; named for the class of proteins in which it was first recognized [54]) domains also coordinate two zinc atoms. For RING and PHD domains, however, the two sets of zinc ligands are not sequential, but instead are interdigitated (Figure 1c) or ‘cross-braced’.
Fan-TAZ-tically different
TAZ (‘transcriptional adaptor zinc-binding’) domains seem to exist only in the transcriptional coactivator CBP, where two ZnFs form a fold that is unrelated to all other ZnFs [70]: namely, three zinc atoms are present in a triangular structure, where each zinc atom is present in a loop region between two antiparallel α helices (Figure 1d).
CBP is an acetyltransferase that is recruited to DNA through interactions with a wide array of DNA-binding transcription factors [71]. The TAZ domains are
Concluding remarks
Although a model of ZnFs as DNA-binding domains was established after their early characterization, numerous recent studies have confirmed that a major function of many classes of ZnFs is to function as protein recognition modules. Indeed, even in the classes of ZnFs for which DNA-binding activity is well established (e.g. GATA-type and classical ZnFs), several protein recognition events have now been observed. Given that the functions of many thousands of classical ZnFs have not been
Acknowledgements
R.G. is supported by a fellowship from the Austrian Science Fund (J2474). C.K.L. is a C.J. Martin Fellow of the National Health and Medical Research Council (NHMRC) and F.E.L. holds an Australian Postgraduate Award. J.P.M. is an NHMRC Senior Research Fellow. This work was supported by an NHMRC Program Grant to J.P.M. and M.C.
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Authors contributed equally.