Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.27.4 (ribonuclease)
 6,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly(A)-specific ribonuclease (PARN), a member of the DEDD family, is a key enzyme involved in the deadenylation of mRNA in higher eukaryotic cells. In this research, it was found that Mg(2+) could protect PARN against thermal inactivation by increasing the midpoint of inactivation and decreasing the inactivation rate. This protective effect was unique to Mg(2+) in a concentration-dependent manner. However, the thermal unfolding and aggregation was promoted by the addition of Mg(2+) at high temperatures. These results revealed that Mg(2+) might have dual effects on PARN stability: protecting the active site but endangering the overall structural stability.
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PMID:Effect of magnesium ions on the thermal stability of human poly(A)-specific ribonuclease. 1730 97

Poly(A) specific ribonuclease (PARN), which contains a catalytic domain and two RNA-binding domains (R3H and RRM), acts as a key enzyme in eukaryotic organisms to regulate the stability of mRNA by degrading the 3' poly-(A) tail. In this research, the activity, structure and stability were compared between the full-length 74kDa PARN, the proteolytic 54kDa fragment with half of the RRM, and a truncated 46kDa form completely missing the RRM. The results indicated that the 46kDa one had the lowest activity and substrate binding affinity, the most hydrophobic exposure in the native state and the least stability upon denaturation. The dissimilarity in the activity, structure and stability of the three PARNs revealed that the entire RRM domain not only contributed to the substrate binding and efficient catalysis of PARN, but also stabilized the overall structures of the protein. Spectroscopic experiments suggested that the RRM domain might be structurally adjacent to the R3H domain, and thus provide a basis for the cooperative binding of poly(A) by the two RNA-binding domains as well as the catalytic domain.
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PMID:Role of the RRM domain in the activity, structure and stability of poly(A)-specific ribonuclease. 1739 38

Eukaryotic mRNAs can be degraded in either decapping/5'-to-3' or 3'-to-5' direction after deadenylation. In yeast and mammalian cells, decay factors involved in the 5'-to-3' decay pathway are concentrated in cytoplasmic processing bodies (P bodies). The mechanistic steps and localization of mammalian mRNA decay are still not completely understood. Here, we investigate functions of human mRNA decay enzymes in AU-rich element (ARE)-mediated mRNA decay (AMD) and find that the deadenylase, poly(A) ribonuclease PARN, and enzymes involved in the 5'-to-3' and 3'-to-5' decay pathways are required for AMD. The ARE-containing reporter mRNA accumulates in discrete cytoplasmic granular structures, which are distinct from P bodies and stress granules. These granules consist of poly(A)-specific ribonuclease, exosome subunits, and decay-promoting ARE-binding proteins. Inhibition of AMD increases accumulation of ARE-mRNA in these granules. We refer to these structures as cytoplasmic exosome granules and suggest that some AMD may occur in these granules.
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PMID:Localization of AU-rich element-containing mRNA in cytoplasmic granules containing exosome subunits. 1747 Apr 29

Poly(A)-specific ribonuclease (PARN), a key enzyme involved in eukaryotic mRNA decay, contains one catalytic domain and two RNA-binding domains. Here we found that at least one RNA-binding domain is required for the substrate binding, but not for the catalysis of PARN. The removal of the R3H domain led to a dramatic decrease in PARN stability and a change in the aggregation kinetic regime, while only minor effects were observed for the removal of the RRM domain or both RNA-binding domains. Thus the R3H domain might stabilize PARN by acting as a protector or intermolecular chaperone of the RRM domain.
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PMID:The R3H domain stabilizes poly(A)-specific ribonuclease by stabilizing the RRM domain. 1762 2

Poly(A)-specific ribonuclease (PARN) is an oligomeric, processive and cap-interacting 3' exoribonuclease that efficiently degrades mRNA poly(A) tails. Here we show that the RNA recognition motif (RRM) of PARN harbors both poly(A) and cap binding properties, suggesting that the RRM plays an important role for the two critical and unique properties that are tightly associated with PARN activity, i.e. recognition and dependence on both the cap structure and poly(A) tail during poly(A) hydrolysis. We show that PARN and its RRM have micromolar affinity to the cap structure by using fluorescence spectroscopy and nanomolar affinity for poly(A) by using filter binding assay. We have identified one tryptophan residue within the RRM that is essential for cap binding but not required for poly(A) binding, suggesting that the cap- and poly(A)-binding sites associated with the RRM are both structurally and functionally separate from each other. RRM is one of the most commonly occurring RNA-binding domains identified so far, suggesting that other RRMs may have both cap and RNA binding properties just as the RRM of PARN.
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PMID:A multifunctional RNA recognition motif in poly(A)-specific ribonuclease with cap and poly(A) binding properties. 1778 61

The degradation of the poly(A) tail is crucial for posttranscriptional gene regulation and for quality control of mRNA. Poly(A)-specific ribonuclease (PARN) is one of the major mammalian 3' specific exo-ribonucleases involved in the degradation of the mRNA poly(A) tail, and it is also involved in the regulation of translation in early embryonic development. The interaction between PARN and the m(7)GpppG cap of mRNA plays a key role in stimulating the rate of deadenylation. Here we report the solution structures of the cap-binding domain of mouse PARN with and without the m(7)GpppG cap analog. The structure of the cap-binding domain adopts the RNA recognition motif (RRM) with a characteristic alpha-helical extension at its C-terminus, which covers the beta-sheet surface (hereafter referred to as PARN RRM). In the complex structure of PARN RRM with the cap analog, the base of the N(7)-methyl guanosine (m(7)G) of the cap analog stacks with the solvent-exposed aromatic side chain of the distinctive tryptophan residue 468, located at the C-terminal end of the second beta-strand. These unique structural features in PARN RRM reveal a novel cap-binding mode, which is distinct from the nucleotide recognition mode of the canonical RRM domains.
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PMID:The RRM domain of poly(A)-specific ribonuclease has a noncanonical binding site for mRNA cap analog recognition. 1864 16

Poly(A)-specific ribonuclease (PARN) is a processive 3'-exoribonuclease involved in the decay of eukaryotic mRNAs. Interestingly, PARN interacts not only with the 3' end of the mRNA but also with its 5' end as PARN contains an RRM domain that specifically binds both the poly(A) tail and the 7-methylguanosine (m(7)G) cap. The interaction of PARN with the 5' cap of mRNAs stimulates the deadenylation activity and enhances the processivity of this reaction. We have determined the crystal structure of the PARN-RRM domain with a bound m(7)G triphosphate nucleotide, revealing a novel binding mode for the m(7)G cap. The structure of the m(7)G binding pocket is located outside of the canonical RNA-binding surface of the RRM domain and differs significantly from that of other m(7)G-cap-binding proteins. The crystal structure also shows a remarkable conformational flexibility of the RRM domain, leading to a perfect exchange of two alpha-helices with an adjacent protein molecule in the crystal lattice.
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PMID:Crystal structure of the RRM domain of poly(A)-specific ribonuclease reveals a novel m(7)G-cap-binding mode. 1869 59

Poly(A)-specific ribonuclease (PARN) is a cap-interacting and poly(A)-specific 3'-exoribonuclease that efficiently degrades mRNA poly(A) tails. Based on the enzyme's preference for its natural substrates, we examined the role of purine nucleotides as potent effectors of human PARN activity. We found that all purine nucleotides tested can reduce poly(A) degradation by PARN. Detailed kinetic analysis revealed that RTP nucleotides behave as non-competitive inhibitors while RDP and RMP exhibit competitive inhibition. Mg(2 + ) which is a catalytically important mediator of PARN activity can release inhibition of RTP and RDP but not RMP. Although many strategies have been proposed for the regulation of PARN activity, very little is known about the modulation of PARN activity by small molecule effectors, such as nucleotides. Our data imply that PARN activity can be modulated by purine nucleotides in vitro, providing an additional simple regulatory mechanism.
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PMID:Inhibition of human poly(A)-specific ribonuclease (PARN) by purine nucleotides: kinetic analysis. 1876 68

Poly(A)-specific ribonuclease (PARN), a multi-domain dimeric enzyme, is a deadenylase in higher vertebrates and plants with the unique property of cap-dependent catalysis and processivity. We found that PARN is an allosteric enzyme, and potassium ions and the cap analogue were effectors with binding sites located at the RRM domain. The binding of K(+) to the entire RRM domain led to an increase of substrate-binding affinity but a decrease in the cooperativity of the substrate-binding site, while the binding of the cap analogue decreased both the catalytic efficiency and the substrate-binding affinity. The dissimilar kinetic properties of the enzymes with and without the entire RRM domain suggested that the RRM domain played a central role in the allosteric communications of PARN regulation. The allostery is proposed to be important to the multi-level regulation of PARN to achieve precise control of the mRNA poly(A) tail length.
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PMID:Allosteric regulation of human poly(A)-specific ribonuclease by cap and potassium ions. 1910 58

Poly(A)-specific ribonuclease (PARN) is a homodimeric, processive, and cap-interacting 3' exoribonuclease that efficiently degrades eukaryotic mRNA poly(A) tails. The crystal structure of a C-terminally truncated PARN in complex with m(7)GpppG reveals that, in one subunit, m(7)GpppG binds to a cavity formed by the RRM domain and the nuclease domain, whereas in the other subunit, it binds almost exclusively to the RRM domain. Importantly, our structural and competition data show that the cap-binding site overlaps with the active site in the nuclease domain. Mutational analysis demonstrates that residues involved in m(7)G recognition are crucial for cap-stimulated deadenylation activity, and those involved in both cap and poly(A) binding are important for catalysis. A modeled PARN, which shows that the RRM domain from one subunit and the R3H domain from the other subunit enclose the active site, provides a structural foundation for further studies to elucidate the mechanism of PARN-mediated deadenylation.
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PMID:Structural basis of m(7)GpppG binding to poly(A)-specific ribonuclease. 1921 98


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