Protein Toxins That Utilize Gangliosides as Host Receptors

Abstract

Subsets of protein toxins utilize gangliosides as host receptors. Gangliosides are preferred receptors due to their extracellular localization on the eukaryotic cell and due to their essential nature in host physiology. Glycosphingolipids, including gangliosides, are mediators of signal transduction within and between eukaryotic cells. Protein toxins possess AB structure-function organization, where the A domain encodes a catalytic function for the posttranslational modification of a host macromolecule, including proteins and nucleic acids, and a B domain, which encodes host receptor recognition, including proteins and glycosphingolipids, alone or in combination. Protein toxins use similar strategies to bind glycans by pockets and loops, generally employing hydrogen bonding and aromatic stacking to stabilize interactions with sugars. In some cases, glycan binding facilitates uptake, while in other cases, cross-linking or a second receptor is necessary to stimulate entry. The affinity that protein toxins have for host glycans is necessary for tissue targeting, but not always sufficient to cause disease. In addition to affinity for binding the glycan, the lipid moiety also plays an important role in productive uptake and tissue tropism. Upon endocytosis, the protein toxin must escape to another intracellular compartment or into cytosol to modify a host substrate, modulating host signaling, often resulting in cytotoxic or apoptotic events in the cell, and a unique morbidity for the organism. The study of protein toxins that utilize gangliosides as host receptors has illuminated numerous eukaryotic cellular processes, identified the basis for developing interventions to prevent disease through vaccines and control bacterial diseases through therapies. In addition, subsets of these protein toxins have been utilized as therapeutic agents to treat numerous human inflictions.

Glycosphingolipids and Infection. Potential New Therapeutic Avenues

“…Protein toxins show an AB structure, with a catalytic A domain and a B domain encoding host receptor recognition (Zuverink and Barbieri, 2018). Gb3, (a.k.a.…”

Organization of gangliosides into membrane nanodomains

“…The qualitative and/or quantitative impairment of the proper ganglioside presentation patterns, and thus the disruption of their physiological interactions, has been associated with distinct human health problems, including several lysosomal storage diseases (e.g. gangliosidosis, Gaucher, Tay-Sachs and Sandhoff [53,54]), Huntington's [55][56][57], Parkinson's [58][59][60] and Alzheimer's [8,[61][62][63][64] diseases, Guillain-Barr e syndrome [65], cancer progression [35,66,67], insulin sensitivity and diabetes [68,69], rare hereditary paraplegia and intellectual disability [70] and bacterial toxin susceptibility [71]. Thorough accounts of the biological functions of gangliosides in health and disease can be found elsewhere [47,72,73].…”

Critical Issues in the Development of Immunotoxins for Anticancer Therapy

“…In addition, this review is intended to provide guidance on the design and development of next-generation ITs. Other topics, such as the mechanisms of action of bacteria-and plant-derived and human toxins 7,[15][16][17] and structural and functional properties of individual ITs, 4,13,15,18 have been comprehensively reviewed elsewhere and are beyond the scope of this article.…”

“…Nonhuman (bacterial and plant) toxins have evolved to kill mammalian cells by entering a broad spectrum of cell types through the cell-binding domain or motif binding to host receptors, such as glycoproteins and glycolipids, ubiquitously expressed in most cells and tissues. 10,17 For example, bacterial DT, PE, and Shiga family toxins utilize heparin-binding epidermal growth factorelike growth factor precursor, 55 a2-macroglobulin receptor, 56 and glycolipid globotriaosylceramide (Gb3) 57 as host receptors, respectively. In the case of plant toxins, such as ricin and abrin, they also utilize any glycoproteins and glycolipids as receptors by binding to the carbohydrate moiety.…”