Summary: ZPR1 zinc-finger domain
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ZPR1 zinc-finger domain Provide feedback
The zinc-finger protein ZPR1 is ubiquitous among eukaryotes. It is indeed known to be an essential protein in yeast. In quiescent cells, ZPR1 is localised to the cytoplasm. But in proliferating cells treated with EGF or with other mitogens, ZPR1 accumulates in the nucleolus. ZPR1 interacts with the cytoplasmic domain of the inactive EGF receptor (EGFR) and is thought to inhibit the basal protein tyrosine kinase activity of EGFR. This interaction is disrupted when cells are treated with EGF, though by themselves, inactive EGFRs are not sufficient to sequester ZPR1 to the cytoplasm [1,2,3]. Upon stimulation by EGF, ZPR1 directly binds the eukaryotic translation elongation factor-1alpha (eEF-1alpha) to form ZPR1/eEF-1alpha complexes . These move into the nucleus, localising particularly at the nucleolus. Indeed, the interaction between ZPR1 and eEF-1alpha has been shown to be essential for normal cellular proliferation  and ZPR1 is thought to be involved in pre-ribosomal RNA expression . The ZPR1 domain consists of an elongation initiation factor 2-like zinc finger and a double-stranded beta helix with a helical hairpin insertion. ZPR1 binds preferentially to GDP-bound eEF1A but does not directly influence the kinetics of nucleotide exchange or GTP hydrolysis . The alignment for this family shows a domain of which there are two copies in ZPR1 proteins. This family also includes several hypothetical archaeal proteins (from both Crenarchaeota and Euryarchaeota), which only contain one copy of the aligned region. This similarity between ZPR1 and archaeal proteins was not previously noted.
Gangwani L, Mikrut M, Galcheva-Gargova Z, Davis RJ; , J Cell Biol 1998;143:1471-1484.: Interaction of ZPR1 with translation elongation factor-1alpha in proliferating cells. PUBMED:9852145 EPMC:9852145
Galcheva-Gargova Z, Gangwani L, Konstantinov KN, Mikrut M, Theroux SJ, Enoch T, Davis RJ; , Mol Biol Cell 1998;9:2963-2971.: The cytoplasmic zinc finger protein ZPR1 accumulates in the nucleolus of proliferating cells. PUBMED:9763455 EPMC:9763455
Galcheva-Gargova Z, Konstantinov KN, Wu IH, Klier FG, Barrett T, Davis RJ; , Science 1996;272:1797-1802.: Binding of zinc finger protein ZPR1 to the epidermal growth factor receptor. PUBMED:8650580 EPMC:8650580
Mishra AK, Gangwani L, Davis RJ, Lambright DG; , Proc Natl Acad Sci U S A. 2007;104:13930-13935.: Structural insights into the interaction of the evolutionarily conserved ZPR1 domain tandem with eukaryotic EF1A, receptors, and SMN complexes. PUBMED:17704259 EPMC:17704259
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR004457
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 ZPR1-type zinc finger domains. An orthologous protein found once in each of the completed archaeal genomes corresponds to a zinc finger-containing domain repeated as the N-terminal and C-terminal halves of the mouse protein ZPR1. ZPR1 is an experimentally proven zinc-binding protein that binds the tyrosine kinase domain of the epidermal growth factor receptor (EGFR); binding is inhibited by EGF stimulation and tyrosine phosphorylation, and activation by EGF is followed by some redistribution of ZPR1 to the nucleus. By analogy, other proteins with the ZPR1 zinc finger domain may be regulatory proteins that sense protein phosphorylation state and/or participate in signal transduction (see also INTERPRO).
Deficiencies in ZPR1 may contribute to neurodegenerative disorders. ZPR1 appears to be down-regulated in patients with spinal muscular atrophy (SMA), a disease characterised by degeneration of the alpha-motor neurons in the spinal cord that can arise from mutations affecting the expression of Survival Motor Neurons (SMN) [PUBMED:16648254]. ZPR1 interacts with complexes formed by SMN [PUBMED:17068332], and may act as a modifier that effects the severity of SMA.
More information about these proteins can be found at Protein of the Month: Zinc Fingers [PUBMED:].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||zinc ion binding (GO:0008270)|
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|Seed source:||Pfam-B_1372 (release 6.6)|
|Number in seed:||14|
|Number in full:||842|
|Average length of the domain:||154.90 aa|
|Average identity of full alignment:||34 %|
|Average coverage of the sequence by the domain:||67.74 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||8|
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the zf-ZPR1 domain has been found. There are 2 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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