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ribonuclease ribotoxin

Miriam Olombrada, Rodrigo Lázaro-Gorines, Juan C López-Rodríguez, Álvaro Martínez-Del-Pozo, Mercedes Oñaderra, Moisés Maestro-López, Javier Lacadena, José G Gavilanes, Lucía García-Ortega
Fungi establish a complex network of biological interactions with other organisms in nature. In many cases, these involve the production of toxins for survival or colonization purposes. Among these toxins, ribotoxins stand out as promising candidates for their use in biotechnological applications. They constitute a group of highly specific extracellular ribonucleases that target a universally conserved sequence of RNA in the ribosome, the sarcin-ricin loop. The detailed molecular study of this family of toxic proteins over the past decades has highlighted their potential in applied research...
February 21, 2017: Toxins
Tim D Jones, Arron R Hearn, Robert G E Holgate, Dorota Kozub, Mark H Fogg, Francis J Carr, Matthew P Baker, Javier Lacadena, Kurt R Gehlsen
Fungal ribotoxins that block protein synthesis can be useful warheads in the context of a targeted immunotoxin. α-Sarcin is a small (17 kDa) fungal ribonuclease produced by Aspergillus giganteus that functions by catalytically cleaving a single phosphodiester bond in the sarcin-ricin loop of the large ribosomal subunit, thus making the ribosome unrecognisable to elongation factors and leading to inhibition of protein synthesis. Peptide mapping using an ex vivo human T cell assay determined that α-sarcin contained two T cell epitopes; one in the N-terminal 20 amino acids and the other in the C-terminal 20 amino acids...
August 29, 2016: Protein Engineering, Design & Selection: PEDS
Miriam Olombrada, Pilar Medina, Flor Budia, José G Gavilanes, Álvaro Martínez-Del-Pozo, Lucía García-Ortega
Metarhizium anisopliae is an entomopathogenic fungus relevant in biotechnology with applications like malaria vector control. Studies of its virulence factors are therefore of great interest. Fungal ribotoxins are toxic ribonucleases with extraordinary efficiency against ribosomes and suggested as potential insecticides. Here we describe this ribotoxin characteristic activity in M. anisopliae cultures. Anisoplin has been obtained as a recombinant protein and further characterized. It is structurally similar to hirsutellin A, the ribotoxin from the entomopathogen Hirsutella thompsonii...
January 1, 2017: Biological Chemistry
Miriam Olombrada, Lucía García-Ortega, Javier Lacadena, Mercedes Oñaderra, José G Gavilanes, Álvaro Martínez-del-Pozo
Ribotoxins are cytotoxic members of the family of fungal extracellular ribonucleases best represented by RNase T1. They share a high degree of sequence identity and a common structural fold, including the geometric arrangement of their active sites. However, ribotoxins are larger, with a well-defined N-terminal β-hairpin, and display longer and positively charged unstructured loops. These structural differences account for their cytotoxic properties. Unexpectedly, the discovery of hirsutellin A (HtA), a ribotoxin produced by the invertebrate pathogen Hirsutella thompsonii, showed how it was possible to accommodate these features into a shorter amino acid sequence...
January 1, 2016: Biological Chemistry
Santosh K Yadav, Janendra K Batra
Restrictocin, a highly specific ribonuclease produced by Aspergillus restrictus, cleaves a single phosphodiester bond in a universally conserved stem and loop structure termed sarcin/ricin loop within the large ribosomal RNA of all organisms. In the current study, we demonstrate restrictocin to manifest anti-HIV-1 activity in two model cell systems. Using two mutants of restrictocin, we further show that the anti-HIV-1 activity of restrictocin is due to its specific ribonucleolytic activity. The study suggests that restrictocin is able to recognize region(s) within HIV-1 genome as its target...
May 2015: International Journal of Biological Macromolecules
Miriam Olombrada, Alvaro Martínez-del-Pozo, Pilar Medina, Flor Budia, José G Gavilanes, Lucía García-Ortega
Ribotoxins are fungal extracellular ribonucleases highly toxic due to their ability to enter host cells and their effective ribonucleolytic activity against the ribosome. The natural role of these proteins in the producing fungi is still unsolved. Nevertheless, recent studies showing the insecticidal properties of two ribotoxins from different origin support their involvement in defense mechanisms. Thus, it seems that not just the entomopathogen Hirsutella thompsonii expresses the ribotoxin hirsutellin A as a virulence factor but also Aspergillus, the main ribotoxin producer, does so...
June 2014: Toxicon: Official Journal of the International Society on Toxinology
Miriam Olombrada, Elías Herrero-Galán, Daniel Tello, Mercedes Oñaderra, José G Gavilanes, Álvaro Martínez-del-Pozo, Lucía García-Ortega
Fungal ribotoxins were discovered almost 50 years ago as extracellular ribonucleases (RNases) with antitumoral properties. However, the biological function of these toxic proteins has remained elusive. The discovery of the ribotoxin HtA, produced by the invertebrates pathogen Hirsutella thompsonii, revived the old proposal that insecticidal activity would be their long searched function. Unfortunately, HtA is rather singular among all ribotoxins known in terms of sequence and structure similarities. Thus, it was intriguing to answer the question of whether HtA is just an exception or, on the contrary, the paradigmatic example of the ribotoxins function...
January 2013: Insect Biochemistry and Molecular Biology
Birthe Meineke, Stewart Shuman
Breakage of tRNA by Escherichia coli anticodon nuclease PrrC (EcoPrrC) underlies a host antiviral response to phage T4 infection. Expression of EcoPrrC is cytocidal in yeast, signifying that PrrC ribotoxicity crosses phylogenetic domain boundaries. EcoPrrC consists of an N-terminal NTPase module that resembles ABC transporters and a C-terminal nuclease module that is sui generis. PrrC homologs are prevalent in many other bacteria. Here we report that Haemophilus influenzae PrrC is toxic in E. coli and yeast...
June 5, 2012: Virology
Elías Herrero-Galán, Lucía García-Ortega, Javier Lacadena, Alvaro Martínez-Del-Pozo, Nieves Olmo, José G Gavilanes, Mercedes Oñaderra
Ribotoxins are fungal extracellular ribonucleases that specifically cleave ribosomes leading to cell-death via apoptosis. α-Sarcin is the ribotoxin studied in deepest detail, and therefore constitutes the referential protein for the whole family. It has been demonstrated that ribotoxin activity depends on a very precise structural microenvironment in which electrostatic interactions among residues in the active site are of the highest importance. Hirsutellin A (HtA) has been recently described as the smallest ribotoxin known to date, encompassing all the abilities of previously characterized members of this family into a shorter sequence...
February 2012: Biochimie
Alice Zhabokritsky, Meherzad Kutky, Lydia A Burns, Rajita A Karran, Katalin A Hudak
RNA toxins are a group of enzymes primarily synthesized by bacteria, fungi, and plants that either cleave or depurinate RNA molecules. These proteins may be divided according to their RNA substrates: ribotoxins are nucleases that cleave ribosomal RNA (rRNA), ribosome inactivating proteins are glycosidases that remove a base from rRNA, messenger RNA (mRNA) interferases are nucleases that cleave mRNAs, and anticodon nucleases cleave transfer RNAs (tRNAs). These modifications to the RNAs may substantially alter gene expression and translation rates...
November 2011: Wiley Interdisciplinary Reviews. RNA
Elisa Alvarez-García, Elizabeth Diago-Navarro, Elías Herrero-Galán, Lucía García-Ortega, Juan López-Villarejo, Nieves Olmo, Ramón Díaz-Orejas, José G Gavilanes, Alvaro Martínez-del-Pozo
Fungal ribotoxins are toxic secreted ribonucleases that cleave a conserved single phosphodiester bond located at the sarcin/ricin loop of the larger rRNA. This cleavage inactivates ribosomes leading to protein biosynthesis inhibition and cell death. It has been proposed that interactions other than those found at the active site of ribotoxins are needed to explain their exquisite specific activity. The study presented shows the ability of a catalytically inactive α-sarcin mutant (H137Q) to bind eukaryotic ribosomes and interfere with in vitro protein biosynthesis...
October 2011: Biochimica et Biophysica Acta
Matthew J Plantinga, Alexei V Korennykh, Joseph A Piccirilli, Carl C Correll
Restrictocin and related fungal endoribonucleases from the α-sarcin family site-specifically cleave the sarcin/ricin loop (SRL) on the ribosome to inhibit translation and ultimately trigger cell death. Previous studies showed that the SRL folds into a bulged-G motif and tetraloop, with restrictocin achieving a specificity of ∼1000-fold by recognizing both motifs only after the initial binding step. Here, we identify contacts within the protein-RNA interface and determine the extent to which each one contributes to enzyme specificity by examining the effect of protein mutations on the cleavage of the SRL substrate compared to a variety of other RNA substrates...
April 12, 2011: Biochemistry
Birthe Meineke, Beate Schwer, Raffael Schaffrath, Stewart Shuman
tRNA damage inflicted by the Escherichia coli anticodon nuclease PrrC (EcoPrrC) underlies an antiviral response to phage T4 infection. PrrC homologs are present in many bacterial proteomes, though their biological activities are uncharted. PrrCs consist of two domains: an N-terminal NTPase module related to the ABC family and a distinctive C-terminal ribonuclease module. In this article, we report that the expression of EcoPrrC in budding yeast is fungicidal, signifying that PrrC is toxic in a eukaryon in the absence of other bacterial or viral proteins...
January 2011: Nucleic Acids Research
Edward Pichinuk, Daniel H Wreschner
We report structural, functional, and biochemical similarities between Argonautes, the effector proteins of RNA-induced silencing complexes (RISCs), and alpha-sarcin-like ribotoxins. At the structural level, regions of similarity in the amino acid sequence are located in protein loops both in the ribotoxins and in the Argonautes. In ribotoxins, these protein loops confer specificity for a highly conserved segment of ribosomal RNA, the Sarcin-Ricin-Loop (SRL) that undergoes cleavage by the ribotoxin ribonuclease...
June 2010: Protein Science: a Publication of the Protein Society
Niroshika Keppetipola, Ruchi Jain, Birthe Meineke, Melinda Diver, Stewart Shuman
tRNA anticodon damage inflicted by secreted ribotoxins such as Kluyveromyces lactis gamma-toxin and bacterial colicins underlies a rudimentary innate immune system that distinguishes self from nonself species. The intracellular expression of gamma-toxin (a 232-amino acid polypeptide) arrests the growth of Saccharomyces cerevisiae by incising a single RNA phosphodiester 3' of the modified wobble base of tRNA(Glu). Fungal gamma-toxin bears no primary structure similarity to any known nuclease and has no plausible homologs in the protein database...
June 2009: RNA
Sanbo Qin, Huan-Xiang Zhou
Restrictocin belongs to a family of site-specific ribonucleases that kill cells by inactivating the ribosome. The restrictocin-ribosome binding rate constant was observed to exceed 10(10) M(-1) s(-1). We have developed a transient-complex theory to model the binding rates of protein-protein and protein-RNA complexes. The theory predicts the rate constant as k(a) = k(a0) exp(-DeltaG(el)*/k(B)T), where k(a0) is the basal rate constant for reaching the transient complex, located at the outer boundary of the bound state, by random diffusion, and DeltaG(el)* is the average electrostatic interaction free energy of the transient complex...
April 28, 2009: Proceedings of the National Academy of Sciences of the United States of America
Nelson Carreras-Sangrà, Elisa Alvarez-García, Elías Herrero-Galán, Jaime Tomé, Javier Lacadena, Jorge Alegre-Cebollada, Mercedes Oñaderra, José G Gavilanes, Alvaro Martínez-Del-Pozo
Ribotoxins constitute a family of toxic extracellular fungal RNases that exert a highly specific activity on a conserved region of the larger molecule of rRNA, known as the sarcin-ricin loop. This cleavage of a single phosphodiester bond inactivates the ribosome and leads to protein synthesis inhibition and cell death. In addition to this ribonucleolytic activity, ribotoxins can cross lipid membranes in the absence of any known protein receptor. This ability is due to their capacity to interact with acid phospholipid-containing membranes...
June 2008: Current Pharmaceutical Biotechnology
Elisa Alvarez-García, Jorge Alegre-Cebollada, Eva Batanero, Vicente Monedero, Gaspar Pérez-Martínez, Rosa García-Fernández, Jose G Gavilanes, Alvaro Martínez del Pozo
Fungal ribotoxins are a family of extracellular ribonucleases which inhibit protein biosynthesis by inactivating the ribosomes. This inactivation results in the induction of cell death by apoptosis. Ribotoxins show antitumoral properties based on their ability to cross the membrane of some transformed cells. Unfortunately, they also show an unspecific cytotoxicity which has greatly impaired their potential clinical uses. alpha-Sarcin, produced by Aspergillus giganteus, is the best-characterized ribotoxin. Asp f 1, another ribotoxin produced by A...
March 20, 2008: Journal of Biotechnology
Elías Herrero-Galán, Javier Lacadena, Alvaro Martínez del Pozo, Drion G Boucias, Nieves Olmo, Mercedes Oñaderra, José G Gavilanes
The mite fungal pathogen Hirsutella thompsonii produces a single polypeptide chain, insecticidal protein named hirsutellin A (HtA) that is composed of 130 amino acid residues. This protein has been purified from its natural source and produced as a recombinant protein in Escherichia coli. Spectroscopic analysis has determined that the two protein forms are indistinguishable. HtA specifically inactivates ribosomes and produces the alpha-fragment characteristic of ribotoxin activity on rRNA. Behaving as a cyclizing ribonuclease, HtA specifically cleaves oligonucleotides that mimick the sarcin/ricin loop of the ribosome, as well as selected polynucleotides and dinucleosides...
July 2008: Proteins
Punyatirtha Dey, Manisha Tripathi, Janendra K Batra
Restrictocin, a member of the fungal ribotoxin family, specifically cleaves a single phosphodiester bond in the 28S rRNA and potently inhibits eukaryotic protein synthesis. The long loops in restrictocin molecule have been shown structurally to be involved in target RNA recognition. In this study we have investigated the role of some putative substrate-interacting residues in loops L2 and L4, spanning residues 36-48 and 99-117, respectively in restrictocin catalysis. The residues Lys42, Ser46, Pro48 and Lys111 were individually mutated to alanine to probe their role in restrictocin function...
2007: Protein and Peptide Letters
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