Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.26.9 (ribonuclease)
 6,589 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Toxin-antitoxin (TA) systems on the chromosomes of free-living bacteria appear to facilitate cell survival during intervals of stress by inducing a state of reversible growth arrest. However, upon prolonged stress, TA toxin action leads to cell death. They have been implicated in several clinically important phenomena--bacterial persistence during antibiotic treatment, biofilm formation and bacterial pathogenesis--and serve as attractive new antibiotic targets for pathogens. We determined the mode of action of the YafQ toxin of the DinJ-YafQ TA system. YafQ expression resulted in inhibition of translation, but not transcription or replication. Purified YafQ exhibited robust ribonuclease activity in vitro that was specifically blocked by the addition of DinJ. However, YafQ associated with ribosomes in vivo and facilitated rapid mRNA degradation near the 5' end via cleavage at AAA lysine codons followed by a G or A. YafQ(H87Q) mutants lost toxicity and cleavage activity but retained ribosome association. Finally, LexA bound to the dinJ-yafQ palindrome and triggered module transcription after DNA damage. YafQ function is distinct from other TA toxins: it associates with the ribosome through the 50S subunit and mediates sequence-specific and frame-dependent mRNA cleavage at (5')AAA-G/A(3') sequences leading to rapid decay possibly facilitated by the mRNA degradosome.
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PMID:Bacterial toxin YafQ is an endoribonuclease that associates with the ribosome and blocks translation elongation through sequence-specific and frame-dependent mRNA cleavage. 1921 Jun 20

In this report, we investigate the efficiency and selectivity of a Zn2+-dependent peptide nucleic acid-based artificial ribonuclease (PNAzyme) that cleaves RNA target sequences. The target RNAs are varied to form different sizes (3 and 4 nucleotides, nt) and sequences in the bulge formed upon binding to the PNAzyme. PNAzyme-promoted cleavage of the target RNAs was observed and variation of the substrate showed a clear dependence on the sequence and size of the bulge. For targets that form 4-nt bulges, we identified systems with an improved efficacy (an estimated half-life of ca 7-8 h as compared to 11-12 h for sequences studied earlier) as well as systems with an improved site selectivity (up to over 70% cleavage at a single site as compared to 50-60% with previous targets sequences). For targets forming 3-nt bulges, the enhancement compared to previous systems was even more pronounced. Compared to a starting point of targets forming 3-nt AAA bulges (half-lives of ca 21-24 h), we could identify target sequences that were cleaved with half-lives three times lower (ca 7-8 h), i.e., at rates similar to those found for the fastest 4-nt bulge system. In addition, with the 3-nt bulge RNA target site selectivity was improved even further to reach well over 80% cleavage at a specific site.
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PMID:Zinc Ion-Dependent Peptide Nucleic Acid-Based Artificial Enzyme that Cleaves RNA-Bulge Size and Sequence Dependence. 2910 68

Schlafen proteins are important in cell differentiation and defense against viruses, and yet this family of vertebrate proteins is just beginning to be understood at the molecular level. Here, the three-dimensional architecture and molecular interfaces of human schlafen12 (hSLFN12), which promotes intestinal stem cell differentiation, are analyzed by sequence conservation and structural modeling in light of the functions of its homologs and binding partners. Our analysis shows that the schlafen or divergent AAA ATPase domain described in the N-terminal region of schlafens in databases and the literature is a misannotation. This N-terminal region is conclusively an AlbA_2 DNA/RNA binding domain, forming the conserved core of schlafens and their sequence homologs from bacteria through mammals. Group III schlafens additionally contain a AAA NTPase domain in their C-terminal helicase region. In hSLFN12, we have uncovered a domain matching rho GTPases, which directly follows the AlbA_2 domain in all group II-III schlafens. Potential roles for the GTPase-like domain include antiviral activity and cytoskeletal interactions that contribute to nucleocytoplasmic shuttling and cell polarization during differentiation. Based on features conserved with rSlfn13, the AlbA_2 region in hSLFN12 is likely to bind RNA, possibly as a ribonuclease. We hypothesize that RNA binding by hSLFN12 contributes to an RNA-induced transcriptional silencing/E3 ligase complex, given the functions of hSLFN12's partners, SUV39H1, JMJD6, and PDLIM7. hSLFN12's partner hSerpinB12 may contribute to heterochromatin formation, based on its homology to MENT, or directly regulate transcription via its binding to RNA polymerase II. The analysis presented here provides clear architectural and transcriptional regulation hypotheses to guide experimental design for hSLFN12 and the thousands of schlafens that share its motifs.
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PMID:Deciphering the three-domain architecture in schlafens and the structures and roles of human schlafen12 and serpinB12 in transcriptional regulation. 3102 79