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  • Title: Structural metal sites in nonclassical zinc finger proteins involved in transcriptional and translational regulation.
    Author: Lee SJ, Michel SL.
    Journal: Acc Chem Res; 2014 Aug 19; 47(8):2643-50. PubMed ID: 25098749.
    Abstract:
    Zinc finger (ZF) proteins are a large family of metalloproteins that utilize zinc for structural purposes. Zinc coordinates to a combination of cysteine thiol and histidine imidazole residues within the ZF polypeptide sequence resulting in a folded and functional protein. Initially, a single class of ZFs were identified. These ZFs, now referred to as the "classical" ZFs, utilize a Cys2His2 (CCHH) ligand set to bind zinc. Upon Zn coordination, the classical ZFs fold into a structure made up of an α helix and an antiparallel β sheet. When folded, classical ZFs recognize and bind to specific DNA targets and function as transcription factors. With the advent of genome sequencing and proteomics, many additional classes of ZFs were identified based upon their primary amino acid sequences. At least 13 additional classes of ZFs are known, and collectively these "nonclassical" ZFs differ in the ligand set involved in Zn(II) coordination, the organization of the ligands within the polypeptide sequence and the macromolecular targets. Some nonclassical ZFs are DNA binding "transcription factors", while others are involved in RNA regulation and protein recognition. Much less is known about these nonclassical ZFs with regards to the roles of metal coordination in fold and function. This Account focuses on our laboratory's efforts to characterize two families of "nonclassical" ZFs: the Cys3His (or CCCH) ZF family and the Cys2His2Cys (or CCHHC) ZF family. Our work on the CCCH ZF family has focused on the protein Tristetraprolin (TTP), which is a key protein in regulating inflammation. TTP contains two CCCH domains that were proposed to be ZFs based upon their sequence. We have shown that while this protein can coordinate Zn(II) at the CCCH sites, it can also coordinate Fe(II) and Fe(III). Moreover, the zinc and iron bound forms of TTP are equally adept at discriminating between RNA targets, which we have demonstrated via a fluorescence anisotropy based approach. Thus, CCCH type ZFs appear to be promiscuous with respect to metal preference and a role for iron coordination in CCCH ZF function is proposed. The CCHHC family of ZFs is a small family of nonclassical ZFs that are essential for the development of the central nervous system. There are three ZFs in this family: neural zinc finger factor-1 (NZF-1), myelin transcription factor-1 (MyT1), and suppressor of tumorgenicity 18 (ST18). All three proteins contain multiple clusters of "CCHHC" domains, which are all predicted to be Zn binding domains. We have focused on a tandem-CCHHC domain construct of NZF-1, which recognizes β-RARE DNA, and we have identified key residues required for DNA recognition. Unlike classical ZFs, for which a few conserved residues are required for DNA recognition, the CCHHC class of ZFs utilize a few nonconserved residues to drive DNA recognition leading us to propose a new paradigm for ZF/DNA binding.
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