Spinal muscular atrophy disrupts the interaction of ZPR1 with the SMN protein

Gangwani, Laxman; Mikrut, Monique; Theroux, Steven J.; Sharma, Manoj Kumar; Davis, Roger J.

doi:10.1038/35070059

Cited by 115 publications

(167 citation statements)

References 43 publications

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“…In addition, the endogenous FGF-2 is up-regulated in motoneurons after peripheral nerve lesion (54) and iodinated FGF-2 is specifically transported by motoneurons (55). In a recent study SMN could be linked to a growth factor signal transduction pathway by interacting with the zinc finger protein ZPR1 (56). ZPR1 binds to EGFR and redistributes to the nucleus and Cajal bodies together with SMN in mitogen-treated cells.…”

Section: Discussionmentioning

confidence: 99%

Differential Intranuclear Localization of Fibroblast Growth Factor-2 Isoforms and Specific Interaction with the Survival of Motoneuron Protein

Claus¹,

Döring²,

Gringel³

et al. 2003

Journal of Biological Chemistry

119

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Fibroblast growth factor 2 (FGF-2) is an important modulator of cell growth and differentiation and a neurotrophic factor. FGF-2 occurs in isoforms, at a low molecular weight of 18,000 and at least two high molecular weight forms (21,000 and 23,000), representing alternative translation products from a single mRNA. In addition to its role as an extracellular ligand, FGF-2 localizes to the nuclei of cells. Here we show differential localization of the 18-and 23-kDa isoforms in the nuclei of rat Schwann cells. Whereas the 18-kDa isoform was found in the nucleoli, nucleoplasm, and Cajal bodies, the 23-kDa isoform localized in a punctuate pattern and associates with mitotic chromosomes suggesting different functional roles of the isoforms. Moreover, we show here that the 23-kDa FGF-2 isoform co-immunoprecipitates specifically with the survival of motor neuron protein (SMN). SMN is an assembly and recycling factor of the splicing machinery and locates to the cytoplasm, the nucleoplasm, and nuclear gems, where it co-localizes with 23-kDa FGF-2. Patients with spinal muscular atrophy suffer from fatal degeneration of motoneurons because of mutations and deletions of the gene for the SMN protein.A number of mitogenic growth factors, growth-regulatory proteins, and growth factor receptors have been reported to be localized in the cell nucleus and its substructures: e.g. plateletderived growth factor, fibroblast growth factor-1 (FGF-1), 1 FGF-2, and ciliary neurotrophic factor (1, 2). The data show that nuclear localization is a general phenomenon for some growth factors, suggesting nuclear functions independent of the function as extracellular factors.FGF-2 is a member of the FGF family, which has been shown to mediate a variety of biological processes during development and in the adult organism, including mitogenesis, angiogenesis, chemotaxis, mesoderm induction, and differentiation of various mesoderm-and neuroectoderm-derived cells. FGF-2 as an extracellular ligand is able to bind to high affinity tyrosine transmembrane receptors (FGF receptors, FGFR). FGF-2 has been shown to bind to all four known FGFR, however, with distinct affinities (3).FGF-2 exists in protein isoforms translated from a common messenger RNA by alternative use of AUG (18,000 isoform) and CUG (high molecular weight isoforms 21,000 and 23,000) start codons. The isoforms exert different biological effects when overexpressed in different cell types. Specific effects seen by the 23-kDa isoform but not the 18-kDa isoform after overexpression are reduced spreading of pancreatic cancer cells (4), the ability of NIH 3T3 cells to grow in low serum medium (5), increased radioresistance in HeLa cells (6), growing in serumfree medium of rat AR4 -2J cells (7), and differential effects on binucleation and nuclear morphology of neonatal rat cardiac myocytes (8). We have previously shown that in PC12 cells and rat immortalized Schwann cells, cell growth and morphology are altered after transfection with constructs coding for 18-and 23-kDa FGF-2, respectively (9, 1...

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Section: Discussionmentioning

confidence: 99%

Differential Intranuclear Localization of Fibroblast Growth Factor-2 Isoforms and Specific Interaction with the Survival of Motoneuron Protein

Claus¹,

Döring²,

Gringel³

et al. 2003

Journal of Biological Chemistry

119

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“…74 The C-terminal tail of ZPR1 interacts indirectly with SMN, forming cytoplasmic snRNP-containing complexes. 70 Given that ZPR1, SMN and SPN can be detected in a pre-import RNP complex, 45 and that anti-ZPR1 antibodies co-deplete Sm proteins from cytoplasmic lysates, 62 it appears that ZPR1 is involved in snRNP biogenesis. Although ZPR1 forms complexes with U snRNPs, it is not directly required for SMN nuclear transport in vitro.…”

Section: Smn Import Regulationmentioning

confidence: 99%

“…However, a zinc finger protein called ZPR1 was reported to participate in this process. 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.…”

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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“…The interaction of ZPR1 with SMN complexes is disrupted in cells derived from patients with spinal muscular atrophy (SMA) (3), an autosomal recessive disease linked to mutations in the telomeric copy of the SMN1 gene and characterized by progressive loss of spinal cord motor neurons during early childhood (7,8). Interestingly, ZPR1 is expressed at low levels in patients with severe forms of SMA and at significantly higher levels in unaffected siblings with an identical SMN1 mutation (9).…”

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.…”

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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Spinal muscular atrophy disrupts the interaction of ZPR1 with the SMN protein

Cited by 115 publications

References 43 publications

Differential Intranuclear Localization of Fibroblast Growth Factor-2 Isoforms and Specific Interaction with the Survival of Motoneuron Protein

Differential Intranuclear Localization of Fibroblast Growth Factor-2 Isoforms and Specific Interaction with the Survival of Motoneuron Protein

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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