Interaction of ZPR1 with Translation Elongation Factor-1α in Proliferating Cells

Gangwani, Laxman; Mikrut, Monique; Galcheva-Gargova, Zoya; Davis, Roger J.

doi:10.1083/jcb.143.6.1471

Cited by 108 publications

(127 citation statements)

References 31 publications

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“…Examples of proteins not directly related to elongation that are known to interact with eEF1A are filamentous actin (F-actin) 51 and the zinc finger protein ZPR1, which is associated with eEF1A and translocated to the nucleus upon treatment of quiescent mammalian cells with mitogens or epidermal growth factor. 52 On the other hand, rapid posttranscriptionally mediated up-regulation of eEF1A has been demonstrated following oxidative stress-induced apoptosis (e.g., upon treatment with hydrogen peroxide). 53 Remarkably, apoptosis induced by dehydrodidemnin has been shown to involve generation of oxidative stress, which can be largely prevented by the glutathione peroxidase mimetic ebselen, 54 and the very weak apoptotic response that is evoked in human normal peripheral blood lymphocytes by this agent (100 nM for 24 h) has been shown to be greatly enhanced in leukemic cells or mitogen-stimulated T-lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Structural Basis for the Binding of Didemnins to Human Elongation Factor eEF1A and Rationale for the Potent Antitumor Activity of These Marine Natural Products

et al. 2004

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Didemnins and tamandarins are closely related marine natural products with potent inhibitory effects on protein synthesis and cell viability. On the basis of available biochemical and structural evidence and results from molecular dynamics simulations, a model is proposed that accounts for the strong and selective binding of these compounds to human elongation factor eEF1A in the presence of GTP. We suggest that the p-methoxyphenyl ring of these cyclic depsipeptides is inserted into the same pocket in eEF1A that normally lodges either the 3′ terminal adenine of aminoacylated tRNA, as inferred from two prokaryotic EF-Tu‚GTP‚tRNA complexes, or the aromatic side chain of Phe/Tyr-163 from the nucleotide exchange factor eEF1BR, as observed in several X-ray crystal structures of a yeast eEF1A:eEF1BR complex. This pocket, which has a strong hydrophobic character, is formed by two protruding loops on the surface of eEF1A domain 2. Further stabilization of the bound depsipeptide is brought about by additional crucial interactions involving eEF1A domain 1 in such a way that the molecule fits snugly at the interface between these two domains. In the GDP-bound form of eEF1A, this binding site exists only as two separate halves, which accounts for the much greater affinity of didemnins for the GTP-bound form of this elongation factor. This binding mode is entirely different from those seen in the complexes of the homologous prokaryotic EF-Tu with kirromycin-type antibiotics or the cyclic thiazolyl peptide antibiotic GE2270A. Interestingly, the set of interactions used by didemnins to bind to eEF1A is also distinct from that used by eEF1BR or eEF1B , thus establishing a competition for binding to a common site that goes beyond simple molecular mimicry. The model presented here is consistent with both available biochemical evidence and known structure-activity relationships for these two classes of natural compounds and synthetic analogues and provides fertile ground for future research.

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Section: Discussionmentioning

confidence: 99%

Structural Basis for the Binding of Didemnins to Human Elongation Factor eEF1A and Rationale for the Potent Antitumor Activity of These Marine Natural Products

et al. 2004

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“…70 ZPR1 is an essential, highly-conserved protein in eukaryotes. 71,72 The protein was originally identified as a factor that binds to the cytoplasmic tyrosine kinase domains of epidermal growth factor (EGF)-like receptors in the absence of mitogens. 73 Ligand binding and autophosphorylation of the receptor causes ZPR1 to be released from the receptor and subsequently accumulate in the nucleus.…”

Section: Smn Import Regulationmentioning

confidence: 99%

SMN - A chaperone for nuclear RNP social occasions?

2016

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Survival Motor Neuron (SMN) protein localizes to both the nucleus and the cytoplasm. Cytoplasmic SMN is diffusely localized in large oligomeric complexes with core member proteins, called Gemins. Biochemical and cell biological studies have demonstrated that the SMN complex is required for the cytoplasmic assembly and nuclear transport of Sm-class ribonucleoproteins (RNPs). Nuclear SMN accumulates with spliceosomal small nuclear (sn)RNPs in Cajal bodies, sub-domains involved in multiple facets of snRNP maturation. Thus, the SMN complex forms stable associations with both nuclear and cytoplasmic snRNPs, and plays a critical role in their biogenesis. In this review, we focus on potential functions of the nuclear SMN complex, with particular emphasis on its role within the Cajal body.

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“…Complementation analyses in yeast demonstrate that the ZnF2-B domain module is required for viability, whereas the ZnF1-A domain module is required for normal cell growth and proliferation (2). The interaction with the inactive EGF receptor is mediated by the ZnFs, whereas the binding sites for eEF1A and the SMN complex are located within the ZnF1-A domain and ZnF2-B domain modules, respectively (1)(2)(3).…”

mentioning

confidence: 99%

“…In proliferating cells treated with mitogens or other growth stimuli, ZPR1 binds directly to eukaryotic translation elongation factor 1A (eEF1A) (2), assembles into multiprotein complexes with the survival motor neurons (SMN) protein (3), and accumulates in subnuclear structures (gems and Cajal bodies) (1,3,4). Targeted disruption of the ZPR1 gene in yeast (2) and mice (5) indicates that ZPR1 is essential for viability in diverse eukaryotic organisms. Reduction of ZPR1 expression in mammalian cells by antisense or siRNA knockdown causes defects in transcription, prevents DNA synthesis, and results in an accumulation of cells in the G 1 and G 2 phases of the cell cycle (6).…”

mentioning

confidence: 99%

Structural insights into the interaction of the evolutionarily conserved ZPR1 domain tandem with eukaryotic EF1A, receptors, and SMN complexes

Mishra¹,

Gangwani²,

Davis

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Eukaryotic genomes encode a zinc finger protein (ZPR1) with tandem ZPR1 domains. In response to growth stimuli, ZPR1 assembles into complexes with eukaryotic translation elongation factor 1A (eEF1A) and the survival motor neurons protein. To gain insight into the structural mechanisms underlying the essential function of ZPR1 in diverse organisms, we determined the crystal structure of a ZPR1 domain tandem and characterized the interaction with eEF1A. The ZPR1 domain consists of an elongation initiation factor 2-like zinc finger and a double-stranded ␤ 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. However, ZPR1 efficiently displaces the exchange factor eEF1B␣ from preformed nucleotide-free complexes, suggesting that it may function as a negative regulator of eEF1A activation. Structure-based mutational and complementation analyses reveal a conserved binding epitope for eEF1A that is required for normal cell growth, proliferation, and cell cycle progression. Structural differences between the ZPR1 domains contribute to the observed functional divergence and provide evidence for distinct modalities of interaction with eEF1A and survival motor neuron complexes.growth factor receptor ͉ structure ͉ neurodegeneration ͉ spinal muscular atrophy ͉ cell cycle

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Interaction of ZPR1 with Translation Elongation Factor-1α in Proliferating Cells

Cited by 108 publications

References 31 publications

Structural Basis for the Binding of Didemnins to Human Elongation Factor eEF1A and Rationale for the Potent Antitumor Activity of These Marine Natural Products

Structural Basis for the Binding of Didemnins to Human Elongation Factor eEF1A and Rationale for the Potent Antitumor Activity of These Marine Natural Products

SMN - A chaperone for nuclear RNP social occasions?

Structural insights into the interaction of the evolutionarily conserved ZPR1 domain tandem with eukaryotic EF1A, receptors, and SMN complexes

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