Cytotoxic effects of ricin without an interchain disulfide bond: genetic modification and chemical crosslinking studies

Mohanraj, D.; Ramakrishnan, Sundaram

doi:10.1016/0304-4165(94)00166-u

Cited by 27 publications

(19 citation statements)

References 37 publications

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“…Interestingly, reduced TMX efficiently reduced ricin in vitro and in the presence of 750 μm GSH and 250 μm GSSG, which mimics glutathione concentration in the ER, TMX is even capable of reducing ricin regardless of its initial redox status. Nevertheless, disulfide reduction seems to not be a prerequisite for ricin in vivo toxicity, as RTA/RTB variants artificially generated by chemical Cys-Cys cross-linking induced by bis-maleimidohexane fully retain in vivo toxicity against human ovarian cancer cells (Mohanraj and Ramakrishnan, 1995).…”

Section: Ricinmentioning

confidence: 99%

Redox diversity in ERAD-mediated protein retrotranslocation from the endoplasmic reticulum: a complex puzzle

Suzuki

2015

Biological Chemistry

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Misfolded and incorrectly assembled proteins in the secretory pathway are eliminated by ubiquitylation and proteasomal degradation in a process known as ER-associated degradation (ERAD). Retrotranslocation of diverse substrates including misfolded proteins and viruses occurs through channels in the ER membrane, which are also utilized for host cell penetration by A/B class protein toxins such as cholera toxin, ricin or K28. According to the current view, disulfide-bonded proteins must either be reduced or rearranged to ensure translocation competence and entry into the cytosol from the ER. As the underlying mechanisms are still largely mysterious, we here focus on the redox status and disulfide isomerization of ERAD substrates and the role of oxidoreductases in the essential process of ER-to-cytosol retrotranslocation.

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Section: Ricinmentioning

confidence: 99%

Redox diversity in ERAD-mediated protein retrotranslocation from the endoplasmic reticulum: a complex puzzle

Suzuki

2015

Biological Chemistry

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“…RTX is posttranslationally processed by host glycosylation and activated by cleavage between A and B domains (6,7). The ricin toxin A domain (RTA) is a type II ribosome-inactivating protein with N-glycosidase activity, which depurinates 28S rRNA within the 60S host ribosome (8).…”

Section: T His Commentary Addresses Studies By Mantis and Coworkers mentioning

confidence: 99%

Protein Structure Facilitates High-Resolution Immunological Mapping

Zuverink

Barbieri

2017

Clin Vaccine Immunol

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Select agents (SA) pose unique challenges for licensing vaccines and therapies. In the case of toxin-mediated diseases, HHS assigns guidelines for SA use, oversees vaccine and therapy development, and approves animal models and approaches to identify mechanisms for toxin neutralization. In this commentary, we discuss next-generation vaccines and therapies against ricin toxin and botulinum toxin, which are regulated SA toxins that utilize structure-based approaches for countermeasures to guide rapid response to future biothreats.KEYWORDS botulinum toxin, RTA, RVEc, RiVax, antibodies, mass spectrometry, ricin T his commentary addresses studies by Mantis and coworkers, who in this issue of Clinical and Vaccine Immunology describe the continued mapping of the neutralizing epitopes within ricin toxin (RTX) and relate these studies to current research on the botulinum neurotoxins (BoNTs) (1, 2). Our goal is to provide a perspective on how protein structure has facilitated development of vaccines and therapies against regulated select agent (SA) toxins. An overview of the properties of ricin toxin and botulinum neurotoxin is presented in Fig. 1. Ricin toxin and the botulinum neurotoxins are HHS and USDA Select Agents and Toxins (7 CFR part 331, 9 CFR part 121, and 42 CFR part 73).AB toxin structure/function. AB toxins contain modular domains with distinct functional activities (3). The A domain encodes an enzymatic activity which targets a host protein to modulate host cell physiology, often inactivating a biological process within cells, leading to cell death or occasionally enhancing the action of a cellular process. The B domain often binds a host receptor, such as a protein or glycolipid, via interactions that bind directly to a specific host receptor or that bind a carbohydrate present on a glycosylated host receptor. AB toxins are often synthesized as single-chain proteins in an inactive form and are converted to an active di-chain by proteolysis between the A and B domains, which remain connected by an interchain disulfide (4, 5).RTX is a category B bioterrorism toxigenic lectin enriched in seeds of the castor bean plant Ricinus communis. RTX is posttranslationally processed by host glycosylation and activated by cleavage between A and B domains (6, 7). The ricin toxin A domain (RTA) is a type II ribosome-inactivating protein with N-glycosidase activity, which depurinates 28S rRNA within the 60S host ribosome (8). Depurination stalls protein synthesis and induces a ribotoxic stress response (9). Ricin toxin B domain (RTB) contains at least two homologous lectin binding sites specific for galactose and binds galactose-containing lipids and glycoproteins (10). While binding of galactose results in nonproductive uptake of RTX, binding to mannose moieties on host mannose-containing receptors results in RTX retrograde trafficking to the endoplasmic reticulum, where RTA is delivered into the cytosol to target the ribosome (11). RTX exploits receptors on multiple cell types; therefore, the symptoms vary based ...

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“…The role of Cys residues in the ricin A chain has been investigated in some detail. Replacement of Cys 259 of the ricin A chain by an Ala residue caused a 40-fold reduction in biological activity, most likely because of the unstable association state of the A and B chain of ricin by hydrophobic bonds instead of a disulphide bond (25).…”

Section: Molecular Modelling Of Cys 242 In Iripmentioning

confidence: 99%

Microenvironment of Cysteine 242 in Type-1 Ribosome-Inactivating Protein from Iris

Hao

Damme

Barre

et al. 2000

Biochemical and Biophysical Research Communications

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Cytotoxic effects of ricin without an interchain disulfide bond: genetic modification and chemical crosslinking studies

Cited by 27 publications

References 37 publications

Redox diversity in ERAD-mediated protein retrotranslocation from the endoplasmic reticulum: a complex puzzle

Redox diversity in ERAD-mediated protein retrotranslocation from the endoplasmic reticulum: a complex puzzle

Protein Structure Facilitates High-Resolution Immunological Mapping

Microenvironment of Cysteine 242 in Type-1 Ribosome-Inactivating Protein from Iris

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