ZnF_C2HC

zinc finger

• SMART accession number: SM00343
• Description: -
• Interpro abstract (IPR001878):

  Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates [ (PUBMED:10529348) (PUBMED:15963892) (PUBMED:15718139) (PUBMED:17210253) (PUBMED:12665246) ]. Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. 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. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few [ (PUBMED:11179890) ]. Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.

  This entry represents the CysCysHisCys (CCHC) type zinc finger domains, and have the sequence:

  C-X2-C-X4-H-X4-C
  

  where X can be any amino acid, and number indicates the number of residues. These 18 residues CCHC zinc finger domains are mainly found in the nucleocapsid protein of retroviruses. It is required for viral genome packaging and for early infection process [ (PUBMED:17416621) (PUBMED:17202191) (PUBMED:17029416) ]. It is also found in eukaryotic proteins involved in RNA binding or single-stranded DNA binding [ (PUBMED:15937226) ].

• GO function: nucleic acid binding (GO:0003676), zinc ion binding (GO:0008270)

There are 212035 ZnF_C2HC domains in 145233 proteins in SMART's nrdb database.

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Curtis D, Treiber DK, Tao F, Zamore PD, Williamson JR, Lehmann R
• A CCHC metal-binding domain in Nanos is essential for translational regulation.
• EMBO J. 1997; 16: 834-43

The Drosophila Nanos protein is a localized repressor of hunchback mRNA translation in the early embryo, and is required for the establishment of the anterior-posterior body axis. Analysis of nanos mutants reveals that a small, evolutionarily conserved, C-terminal region is essential for Nanos function in vivo, while no other single portion of the Nanos protein is absolutely required. Within the C-terminal region are two unusual Cys-Cys-His-Cys (CCHC) motifs that are potential zinc-binding sites. Using absorption spectroscopy and NMR we demonstrate that the CCHC motifs each bind one equivalent of zinc with high affinity. nanos mutations disrupting metal binding at either of these two sites in vitro abolish Nanos translational repression activity in vivo. We show that full-length and C-terminal Nanos proteins bind to RNA in vitro with high affinity, but with little sequence specificity. Mutations affecting the hunchback mRNA target sites for Nanos-dependent translational repression were found to disrupt translational repression in vivo, but had little effect on Nanos RNA binding in vitro. Thus, the Nanos zinc domain does not specifically recognize target hunchback RNA sequences, but might interact with RNA in the context of a larger ribonucleoprotein complex.

• Webb JR, McMaster WR
• Molecular cloning and expression of a Leishmania major gene encoding a single-stranded DNA-binding protein containing nine "CCHC" zinc finger motifs.
• J Biol Chem. 1993; 268: 13994-4002

The genes encoding GP63, the major surface glycoprotein of the protozoan parasite Leishmania, are highly conserved across diverse species of Leishmania both within the protein coding region and in the immediate 5'-untranslated region. Located between the 3' trans-spliced leader acceptor site and the translational initiation codon of the GP63 gene is an area of conserved hexanucleotide direct repeats (CTCGCC) which vary in number according to species. To determine whether these repeats represent a site of protein DNA interaction, a Leishmania major lambda gt11 expression library was screened with a radiolabeled synthetic oligodeoxynucleotide probe containing multiple CTCGCC repeats to detect clones expressing functional DNA-binding proteins. Using this approach a gene was isolated which encodes a sequence-specific DNA-binding protein referred to as HEXBP (hexamer-binding protein). Sequence analysis of the HEXBP gene showed that HEXBP contains nine cysteine-rich motifs which are identical to a consensus sequence known as the "CCHC type" zinc finger. This motif is present in a number of nucleic acid-binding proteins including the nucleocapsid protein of retroviruses. In accordance with the activity exhibited by other proteins containing the "CCHC" motif, HEXBP binds to single-stranded nucleic acids as demonstrated by gel mobility shift assays and Southwestern blot assays.

• Summers MF, South TL, Kim B, Hare DR
• High-resolution structure of an HIV zinc fingerlike domain via a new NMR-based distance geometry approach.
• Biochemistry. 1990; 29: 329-40

A new method is described for determining molecular structures from NMR data. The approach utilizes 2D NOESY back-calculations to generate simulated spectra for structures obtained from distance geometry (DG) computations. Comparison of experimental and back-calculated spectra, including analysis of cross-peak buildup and auto-peak decay with increasing mixing time, provides a quantitative measure of the consistence between the experimental data and generated structures and allows for use of tighter interproton distance constraints. For the first time, the "goodness" of the generated structures is evaluated on the basis of their consistence with the actual experimental data rather than on the basis of consistence with other generated structures. This method is applied to the structure determination of an 18-residue peptide with an amino acid sequence comprising the first zinc fingerlike domain from the gag protein p55 of HIV. This is the first structure determination to atomic resolution for a retroviral zinc fingerlike complex. The peptide [Zn(p55F1)] exhibits a novel folding pattern that includes type I and type II NH-S tight turns and is stabilized both by coordination of the three Cys and one His residues to zinc and by extensive internal hydrogen bonding. The backbone folding is significantly different from that of a "classical" DNA-binding zinc finger. Residues C(1)-F(2)-N(3)-C(4)-G(5)-K(6) fold in a manner virtually identical with the folding observed by X-ray crystallography for related residues in the iron domain of rubredoxin; superposition of all main-chain and Cys side-chain atoms of residues C(1)-K(6) of Zn(p55F1) onto residues C(6)-Y(11) and C(39)-V(44) of rubredoxin gives RMSDs of 0.46 and 0.35 A, respectively. The side chains of conservatively substituted Phe and Ile residues implicated in genomic RNA recognition form a hydrophobic patch on the peptide surface.

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
27.08	map00500	Starch and sucrose metabolism
27.08	map00790	Folate biosynthesis
22.92	map03022	Basal transcription factors
16.67	map00230	Purine metabolism
2.08	map04060	Cytokine-cytokine receptor interaction
2.08	map04115	p53 signaling pathway
2.08	map04120	Ubiquitin mediated proteolysis

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with ZnF_C2HC domain which could be assigned to a KEGG orthologous group, and not all proteins containing ZnF_C2HC domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of ZnF_C2HC domains in PDB

PDB code	Title
1a1t	STRUCTURE OF THE HIV-1 NUCLEOCAPSID PROTEIN BOUND TO THE SL3 PSI-RNA RECOGNITION ELEMENT, NMR, 25 STRUCTURES
1a6b	NMR STRUCTURE OF THE COMPLEX BETWEEN THE ZINC FINGER PROTEIN NCP10 OF MOLONEY MURINE LEUKEMIA VIRUS AND A SEQUENCE OF THE PSI-PACKAGING DOMAIN OF HIV-1, 20 STRUCTURES
1aaf	NUCLEOCAPSID ZINC FINGERS DETECTED IN RETROVIRUSES: EXAFS STUDIES ON INTACT VIRUSES AND THE SOLUTION-STATE STRUCTURE OF THE NUCLEOCAPSID PROTEIN FROM HIV-1
1bj6	1H NMR OF (12-53) NCP7/D(ACGCC) COMPLEX, 10 STRUCTURES
1cl4	NUCLEOCAPSID PROTEIN FROM MASON-PFIZER MONKEY VIRUS (MPMV)
1dsq	STRUCTURE OF THE MMTV NUCLEOCAPSID PROTEIN (ZINC FINGER 1)
1dsv	STRUCTURE OF THE MMTV NUCLEOCAPSID PROTEIN (C-TERMINAL ZINC FINGER)
1esk	SOLUTION STRUCTURE OF NCP7 FROM HIV-1
1f6u	NMR structure of the HIV-1 nucleocapsid protein bound to stem-loop sl2 of the psi-RNA packaging signal. Implications for genome recognition
1hvn	ZINC-AND SEQUENCE-DEPENDENT BINDING TO NUCLEIC ACIDS BY THE N-TERMINAL ZINC FINGER DOMAIN OF THE HIV-1 NUCLEOCAPSID PROTEIN: NMR STRUCTURE OF THE COMPLEX WITH THE PSI-SITE ANALOG, D/ACGCC
1hvo	ZINC-AND SEQUENCE-DEPENDENT BINDING TO NUCLEIC ACIDS BY THE N-TERMINAL ZINC FINGER DOMAIN OF THE HIV-1 NUCLEOCAPSID PROTEIN: NMR STRUCTURE OF THE COMPLEX WITH THE PSI-SITE ANALOG, D/ACGCC
1mfs	DYNAMICAL BEHAVIOR OF THE HIV-1 NUCLEOCAPSID PROTEIN; NMR, 30 STRUCTURES
1nc8	HIGH-RESOLUTION SOLUTION NMR STRUCTURE OF THE MINIMAL ACTIVE DOMAIN OF THE HUMAN IMMUNODEFICIENCY VIRUS TYPE-2 NUCLEOCAPSID PROTEIN, 15 STRUCTURES
1ncp	STRUCTURAL CHARACTERIZATION OF A 39 RESIDUE SYNTHETIC PEPTIDE CONTAINING THE TWO ZINC BINDING DOMAINS FROM THE HIV-1 P7 NUCLEOCAPSID PROTEIN BY CD AND NMR SPECTROSCOPY
1q3y	NMR structure of the Cys28His mutant (D form) of the nucleocapsid protein NCp7 of HIV-1.
1q3z	NMR structure of the Cys28His mutant (E form) of the nucleocapsid protein NCp7 of HIV-1.
1u6p	NMR Structure of the MLV encapsidation signal bound to the Nucleocapsid protein
1wwd	NMR structure determined for MLV NC complex with RNA sequence AACAGU
1wwe	NMR Structure Determined for MLV NC complex with RNA Sequence UUUUGCU
1wwf	NMR Structure Determined for MLV NC Complex with RNA Sequence CCUCCGU
1wwg	NMR Structure Determined for MLV NC Complex with RNA Sequence UAUCUG
2a51	Structure of the (13-51) domain of the nucleocapsid protein NCp8 from SIVlhoest
2bl6	Solution structure of the Zn complex of EIAV NCp11(22-58) peptide, including two CCHC Zn-binding motifs.
2cqf	Solution Structure of the Zinc-finger domain in LIN-28
2di2	NMR structure of the HIV-2 nucleocapsid protein
2e1x	NMR structure of the HIV-2 nucleocapsid protein
2ec7	Solution Structure of Human Immunodificiency Virus Type-2 Nucleocapsid Protein
2exf	Solution structure of the HIV-1 nucleocapsid (NCp7(12-55)) complexed with the DNA (-) Primer Binding Site
2hqh	Crystal structure of p150Glued and CLIP-170
2ihx	Solution Structure of the Rous Sarcoma Virus Nucleocapsid Protein:uPsi RNA Packaging Signal Complex
2iwj	SOLUTION STRUCTURE OF THE ZN COMPLEX OF HIV-2 NCP(23-49) PEPTIDE, ENCOMPASSING PROTEIN CCHC-LINKER, DISTAL CCHC ZN-BINDING MOTIF AND C- TERMINAL TAIL.
2jzw	How the HIV-1 nucleocapsid protein binds and destabilises the (-)primer binding site during reverse transcription
2k2c	Solution NMR structure of N-terminal domain of human pirh2. Northeast Structural Genomics Consortium (NESG) target HT2A
2kmk	Gfi-1 Zinc Fingers 3-5 complexed with DNA
2l44	C-terminal zinc knuckle of the HIVNCp7
2l45	C-terminal zinc knuckle of the HIVNCp7 with DNA
2l46	C-terminal zinc finger of the HIVNCp7 with platinated DNA
2l4l	Structural insights into the cTAR DNA recognition by the HIV-1 Nucleocapsid protein: role of sugar deoxyriboses in the binding polarity of NC
2li8	The solution structure of the Lin28-ZnF domains bound to AGGAGAU of pre-let-7 miRNA
2lli	Low resolution structure of RNA-binding subunit of the TRAMP complex
2m3z	NMR solution structure of HIV-1 nucleocapsid protein in complex with an inhibitor displaying a 2 inhibitors:1 NC stoichiometry
2mpj	2MPJ
2mqv	2MQV
2ms0	2MS0
2ms1	2MS1
2ysa	Solution structure of the zinc finger CCHC domain from the human retinoblastoma-binding protein 6 (Retinoblastoma-binding Q protein 1, RBQ-1)
2znf	HIGH-RESOLUTION STRUCTURE OF AN HIV ZINC FINGERLIKE DOMAIN VIA A NEW NMR-BASED DISTANCE GEOMETRY APPROACH
3alr	Crystal structure of Nanos
3e2u	Crystal structure of the zink-knuckle 2 domain of human CLIP-170 in complex with CAP-Gly domain of human dynactin-1 (p150-GLUED)
3nyb	Structure and function of the polymerase core of TRAMP, a RNA surveillance complex
3trz	Mouse Lin28A in complex with let-7d microRNA pre-element
3ts0	Mouse Lin28A in complex with let-7f-1 microRNA pre-element
3ts2	Mouse Lin28A in complex with let-7g microRNA pre-element
4utn	4UTN
4utr	4UTR
4utv	4UTV
4utx	4UTX
4utz	4UTZ
4uu7	4UU7
4uu8	4UU8
4uua	4UUA
4uub	4UUB
5a9e	5A9E
5i1r	5I1R
5kl1	5KL1
5kl8	5KL8

Links (links to other resources describing this domain)

• PFAM: zf-CCHC
• INTERPRO: IPR001878