Review
Sticky fingers: zinc-fingers as protein-recognition motifs

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Zinc-fingers (ZnFs) are extremely abundant in higher eukaryotes. Once considered to function exclusively as sequence-specific DNA-binding motifs, ZnFs are now known to have additional activities such as the recognition of RNA and other proteins. Here we discuss recent advances in our understanding of ZnFs as specific modules for protein recognition. Structural studies of ZnF complexes reveal considerable diversity in terms of protein partners, binding modes and affinities, and highlight the often underestimated versatility of ZnF structure and function. An appreciation of the structural features of ZnF–protein interactions will contribute to our ability to engineer and to use ZnFs with tailored protein-binding properties.

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.

References (82)

  • C.W. Liew

    Molecular analysis of the interaction between the hematopoietic master transcription factors GATA-1 and PU.1

    J. Biol. Chem.

    (2006)
  • F.E. Reyes-Turcu

    The ubiquitin binding domain ZnF UBP recognizes the C-terminal diglycine motif of unanchored ubiquitin

    Cell

    (2006)
  • B. Wang

    Structure and ubiquitin interactions of the conserved zinc finger domain of Npl4

    J. Biol. Chem.

    (2003)
  • C.A. Plambeck

    The structure of the zinc finger domain from human splicing factor ZNF265 fold

    J. Biol. Chem.

    (2003)
  • A.W. Opipari

    The A20 cDNA induced by tumor necrosis factor α encodes a novel type of zinc finger protein

    J. Biol. Chem.

    (1990)
  • R. Mattera

    The Rab5 guanine nucleotide exchange factor Rabex-5 binds ubiquitin (Ub) and functions as a Ub ligase through an atypical Ub-interacting motif and a zinc finger domain

    J. Biol. Chem.

    (2006)
  • L. Penengo

    Crystal structure of the ubiquitin binding domains of Rabex-5 reveals two modes of interaction with ubiquitin

    Cell

    (2006)
  • A. Kanayama

    TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains

    Mol. Cell

    (2004)
  • Z. Xu

    Molecular dissection of PINCH-1 reveals a mechanism of coupling and uncoupling of cell shape modulation and survival

    J. Biol. Chem.

    (2005)
  • A. Velyvis

    Solution structure of the focal adhesion adaptor PINCH LIM1 domain and characterization of its interaction with the integrin-linked kinase ankyrin repeat domain

    J. Biol. Chem.

    (2001)
  • J. Vaynberg

    Structure of an ultraweak protein–protein complex and its crucial role in regulation of cell morphology and motility

    Mol. Cell

    (2005)
  • R. Spadaccini

    Structure and functional analysis of the MYND domain

    J. Mol. Biol.

    (2006)
  • R.J. Sims

    m-Bop, a repressor protein essential for cardiogenesis, interacts with skNAC, a heart- and muscle-specific transcription factor

    J. Biol. Chem.

    (2002)
  • S. Ansieau et al.

    The conserved Mynd domain of BS69 binds cellular and oncoviral proteins through a common PXLXP motif

    J. Biol. Chem.

    (2002)
  • R.B. Dodd

    Solution structure of the Kaposi's sarcoma-associated herpesvirus K3 N-terminal domain reveals a novel E2-binding C4HC3-type RING domain

    J. Biol. Chem.

    (2004)
  • H. Peng

    Reconstitution of the KRAB–KAP-1 repressor complex: a model system for defining the molecular anatomy of RING-B box–coiled-coil domain-mediated protein–protein interactions

    J. Mol. Biol.

    (2000)
  • N. Zheng

    Structure of a c-Cbl–UbcH7 complex: RING domain function in ubiquitin-protein ligases

    Cell

    (2000)
  • F.M. Townsley

    Pygopus residues required for its binding to Legless are critical for transcription and development

    J. Biol. Chem.

    (2004)
  • C.P. Ponting

    ZZ and TAZ: new putative zinc fingers in dystrophin and other proteins

    Trends Biochem. Sci.

    (1996)
  • G.A. Blobel

    CREB-binding protein and p300: molecular integrators of hematopoietic transcription

    Blood

    (2000)
  • A.H. Kwan

    Engineering a protein scaffold from a PHD finger

    Structure.

    (2003)
  • C. Dominguez

    Structural model of the UbcH5B/CNOT4 complex revealed by combining NMR, mutagenesis, and docking approaches

    Structure.

    (2004)
  • Z. Li

    Structure of a Bmi-1–Ring1B polycomb group ubiquitin ligase complex

    J. Biol. Chem.

    (2006)
  • R.N. De Guzman

    Interaction of the TAZ1 domain of the CREB-binding protein with the activation domain of CITED2: regulation by competition between intrinsically unstructured ligands for non-identical binding sites

    J. Biol. Chem.

    (2004)
  • J. Miller

    Repetitive zinc-binding domains in the protein transcription factor IIIA from Xenopus oocytes

    EMBO J.

    (1985)
  • S.A. Wolfe

    DNA recognition by Cys2His2 zinc finger proteins

    Annu. Rev. Biophys. Biomol. Struct.

    (2000)
  • G.M. Rubin

    Comparative genomics of the eukaryotes

    Science

    (2000)
  • S.S. Krishna

    Structural classification of zinc fingers: survey and summary

    Nucleic Acids Res.

    (2003)
  • R. Marmorstein

    DNA recognition by GAL4: structure of a protein–DNA complex

    Nature

    (1992)
  • J.G. Omichinski

    NMR structure of a specific DNA complex of Zn-containing DNA binding domain of GATA-1

    Science

    (1993)
  • D. Lu

    Crystal structure of a zinc-finger–RNA complex reveals two modes of molecular recognition

    Nature

    (2003)
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