Ribotoxins are a more widespread group of proteins within the filamentous fungi than previously believed

Martı́nez-Ruiz, Antonio; Kao, Richard; Davies, Julian; Pozo, Álvaro Martı́nez del

doi:10.1016/s0041-0101(99)00103-8

Cited by 49 publications

(69 citation statements)

References 44 publications

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“…This observation prompted the development of their molecular characterization (Lacadena et al, 2007). Much later, more systematic analysis of fungal genomes revealed that ribotoxins were a more widespread group of proteins within the filamentous fungi than had been previously believed (Lin et al, 1995;Martínez-Ruiz et al, 1999b;Varga and Samson, 2008). All this exhaustive work dealing with the characterization of their mechanism of action at the molecular level has not only helped to understand the basis of their antitumoral action (Lacadena et al, 2007) but also has established the principles to transform some of them into engineered chimeras with potential therapeutic uses (Carreras-Sangrà et al, 2008, 2012.…”

Section: Discussionmentioning

confidence: 99%

“…-Sarcin, restrictocin, and Aspf1 are the most exhaustively characterized ribotoxins (Arruda et al, 1992;García-Ortega et al, 2005;Gasset et al, 1994;Kao et al, 2001;Martínez-Ruiz et al, 2001;Wool, 1997), but many others have been identified and partially characterized within different fungal species (Huang et al,1997;Lin et al, 1995;Martínez-Ruiz et al, 1999a, 1999bParente et al, 1996;Varga and Samson, 2008;Wirth et al, 1997). These studies have shown a high degree of conservation among ribotoxins, as most of those so far characterized display amino acid sequence similarities above 85% (Lacadena et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Fungal extracellular ribotoxins as insecticidal agents

Olombrada¹,

Herrero-Galán²,

Tello³

et al. 2013

Insect Biochemistry and Molecular Biology

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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 H. 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. The work presented uses HtA and -sarcin, the most representative member of the ribotoxins family, to show their strong toxic action against insect larvae and cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fungal extracellular ribotoxins as insecticidal agents

Olombrada¹,

Herrero-Galán²,

Tello³

et al. 2013

Insect Biochemistry and Molecular Biology

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“…Most ribotoxins show a high degree of sequence identity [9][10][11][12] that is also manifested in the three-dimensional structure of the two only ribotoxins studied at this level, restrictocin [13,14] and α-sarcin [15][16][17][18]. Both proteins fold into an α+β structure with a central five-stranded antiparallel β-sheet and an α-helix of almost three turns and display long and unstructured loops ( Fig.1) [ 15,19,20].…”

Section: Introductionmentioning

confidence: 99%

“…This β-hairpin is one of the regions showing the highest sequence variability among ribotoxins [9][10][11][12]21]. An α-sarcin mutant involving the deletion of this protuberance, α-sarcin Δ (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), retained the same conformation as the wildtype protein, as ascertained from its three-dimensional structure in solution [22].…”

Section: Introductionmentioning

confidence: 99%

Role of the basic character of α-sarcin’s NH2-terminal β-hairpin in ribosome recognition and phospholipid interaction

Álvarez-García

Martínez‐del‐Pozo

Gavilanes

2009

Archives of Biochemistry and Biophysics

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Ribotoxins are a family of toxic extracellular fungal RNases that first enter into the cells and then exert a highly specific ribonucleolytic activity on the larger rRNA molecule, leading to protein synthesis inhibition and cell death by apoptosis. α-Sarcin is the best characterized ribotoxin. Previous characterization of a deletion variant of this protein showed that its long NH 2 -terminal β-hairpin is essential for its cytotoxicity. Docking, enzymatic, and lipidprotein interaction studies suggested that this β-hairpin establishes specific interactions with ribosomal proteins and that it is a region involved in the interaction with cell membranes. Consequently, in order to assess the influence of the basic character of this NH 2 -terminal β-hairpin (there are 1 arginine and 4 lysines along its 16 residues) on the ribotoxins cytotoxic ability, five individual mutants substituting these 5 basic residues by glutamic acid were produced, purified to homogeneity, and characterized. Regarding ribosomal recognition, all mutants showed a diminished activity in a cell-free reticulocyte lysate, whereas the activity against an oligoribonucleotide mimicking the sarcin/ricin loop rRNA (SRL) or the homopolymer poly(A) remained unaffected, confirming that the mutated basic residues participate in electrostatic interactions with other ribosomal elements apart from this SRL. The study of the interaction with phospholipid vesicles showed that Lys 17, Arg 22, and, most importantly, Lys 14 and Lys 21, are crucial residues in the first stages of the aggregation phenomenon, where protein-vesicle and protein-protein interactions are required. The data obtained reveal that electrostatic interactions involving basic residues of the β-hairpin are required not only for establishing specific interactions with ribosomal regions other than the SRL but also to explain the ability of the protein to interact with acid phospholipid bilayers.

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“…α-Sarcin, restrictocin, and Asp f 1 are the most exhaustively characterized ribotoxins [1][2][3][4][8][9][10], but many others have been identified and partially characterized in different fungal species [11][12][13][14][15][16], including the insecticidal protein hirsutellin A (HtA) produced by the invertebrate fungal pathogen Hirsutella thompsonii [15,17,18]. All ribotoxins show a high degree of amino acid sequence identity (above 85%) with precisely the only exception of HtA that displays only about 25% sequence identity with the previously known family members [15,18].…”

Section: Introductionmentioning

confidence: 99%

The Therapeutic Potential of Fungal Ribotoxins

Carreras-Sangrà

Álvarez-García²,

Herrero-Galán³

et al. 2008

CPB

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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. Both activities together explain their cytotoxic character, being rather specific when assayed against some transformed cell lines. The determination of highresolution structures of some ribotoxins, the characterization of a large number of mutants, and the use of lipid model vesicles and transformed cell lines have been the tools used for the study of their mechanism of action at the molecular level. The present knowledge suggests that wild-type ribotoxins or some modified variants might be used in human therapies. Production of hypoallergenic mutants and immunotoxins designed against specific tumors stand out as feasible alternatives to treat some human pathology in the midterm future.3

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Ribotoxins are a more widespread group of proteins within the filamentous fungi than previously believed

Cited by 49 publications

References 44 publications

Fungal extracellular ribotoxins as insecticidal agents

Fungal extracellular ribotoxins as insecticidal agents

Role of the basic character of α-sarcin’s NH2-terminal β-hairpin in ribosome recognition and phospholipid interaction

The Therapeutic Potential of Fungal Ribotoxins

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