Structure of trypanosome coat protein VSGsur and function in suramin resistance

Zeelen, J.P.; Straaten, Monique van; Verdi, Joseph; Hempelmann, A.; Hashemi, Hossein; Perez, Kathryn; Jeffrey, Philip D.; Hälg, Silvan; Wiedemar, Natalie; Mäser, Pascal; Papavasiliou, F. Nina; Stebbins, C. Erec

doi:10.1038/s41564-020-00844-1

Cited by 25 publications

(46 citation statements)

References 52 publications

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“…Although the exact mechanism of resistance is unclear, drug internalization via the endocytic lysosomal pathway seems to be reduced [63]. Recent resolution of the tertiary structure of VSG sur by X-ray crystallography revealed that VSG sur binds to suramin, reducing the concentration of bioavailable drug entering the trypanosome cell [64]. Furthermore, newly produced VSG sur has been hypothesized to bind the imported suramin inside the endosome, and to be then trafficked to the cell surface, effectively removing the drug from cells [64].…”

Section: Drug Resistancementioning

confidence: 99%

Evolution of the variant surface glycoprotein family in African trypanosomes

Pereira

Jackson

Figueiredo

2022

Trends in Parasitology

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An intriguing and remarkable feature of African trypanosomes is their antigenic variation system, mediated by the variant surface glycoprotein (VSG) family and fundamental to both immune evasion and disease epidemiology within host populations. Recent studies have revealed that the VSG repertoire has a complex evolutionary history. Sequence diversity, genomic organization, and expression patterns are species-specific, which may explain other variations in parasite virulence and disease pathology. Evidence also shows that we may be underestimating the extent to what VSGs are repurposed beyond their roles as variant antigens, establishing a need to examine VSG functionality more deeply. Here, we review sequence variation within the VSG gene family, and highlight the many opportunities to explore their likely diverse contributions to parasite survival. VSGs are variant antigens key to the survival of African trypanosomesVSGs are major surface antigens of African trypanosomes, extracellular parasites of humans and animals. African trypanosomes alternate between a vector (typically a tsetse fly within Africa, but other blood-sucking insects beyond Africa) and a mammalian host (Box 1). African trypanosomes survive in the mammal using antigenic variation as a mechanism of immune evasion. VSGs are the variant antigens recognized by the host immune system during infection, and their modulation by the parasite can prevent long-lasting immunity (Box 2, and reviewed in [1]). African trypanosome genomes are furnished with several thousand VSG genes, perhaps 10-20% of total gene number, to provide the raw material for antigenic variation. But how has this pool of structural diversity evolved, and why are so many VSG genes required to evade immunity?

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Section: Drug Resistancementioning

confidence: 99%

Evolution of the variant surface glycoprotein family in African trypanosomes

Pereira

Jackson

Figueiredo

2022

Trends in Parasitology

View full text Add to dashboard Cite

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“…Based on studies on the VSG N-terminal domain from the 1990s, VSGs were long thought to invariably form homodimers of very similar structure (Freymann et al, 1990;Blum et al, 1993) with a more recently solved VSG structure also showing very similar structural traits (Bartossek et al, 2017). Other recent findings, however, suggest that the members of the large VSG family are structurally more diverse than previously thought, with some believed to form trimers on the cell surface (Pinger et al, 2018;Umaer et al, 2021;Zeelen et al, 2021). VSG homodimers are attached to the plasma membrane via two GPI anchors, with each one covalently linked to the C-terminus of one monomer (Ferguson et al, 1988).…”

Section: Gpi-anchored Molecules In Mammalian Host Stagesmentioning

confidence: 99%

The Glycosylphosphatidylinositol Anchor: A Linchpin for Cell Surface Versatility of Trypanosomatids

Borges

Link

Engstler

et al. 2021

Front. Cell Dev. Biol.

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The use of glycosylphosphatidylinositol (GPI) to anchor proteins to the cell surface is widespread among eukaryotes. The GPI-anchor is covalently attached to the C-terminus of a protein and mediates the protein’s attachment to the outer leaflet of the lipid bilayer. GPI-anchored proteins have a wide range of functions, including acting as receptors, transporters, and adhesion molecules. In unicellular eukaryotic parasites, abundantly expressed GPI-anchored proteins are major virulence factors, which support infection and survival within distinct host environments. While, for example, the variant surface glycoprotein (VSG) is the major component of the cell surface of the bloodstream form of African trypanosomes, procyclin is the most abundant protein of the procyclic form which is found in the invertebrate host, the tsetse fly vector. Trypanosoma cruzi, on the other hand, expresses a variety of GPI-anchored molecules on their cell surface, such as mucins, that interact with their hosts. The latter is also true for Leishmania, which use GPI anchors to display, amongst others, lipophosphoglycans on their surface. Clearly, GPI-anchoring is a common feature in trypanosomatids and the fact that it has been maintained throughout eukaryote evolution indicates its adaptive value. Here, we explore and discuss GPI anchors as universal evolutionary building blocks that support the great variety of surface molecules of trypanosomatids.

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“…Chebulinic acid is ellagitannin, a plant polyphenol with anticancer activity [61]. Suramin is a bispolysulfonated naphthylurea used for treatment of trypanosomiasis [62] as well as an antineoplastic agent used as a chemosensitizer [63,64].…”

Section: Human Adp/atp Carriermentioning

confidence: 99%

Learning from Yeast about Mitochondrial Carriers

et al. 2021

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Mitochondria are organelles that play an important role in both energetic and synthetic metabolism of eukaryotic cells. The flow of metabolites between the cytosol and mitochondrial matrix is controlled by a set of highly selective carrier proteins localised in the inner mitochondrial membrane. As defects in the transport of these molecules may affect cell metabolism, mutations in genes encoding for mitochondrial carriers are involved in numerous human diseases. Yeast Saccharomyces cerevisiae is a traditional model organism with unprecedented impact on our understanding of many fundamental processes in eukaryotic cells. As such, the yeast is also exceptionally well suited for investigation of mitochondrial carriers. This article reviews the advantages of using yeast to study mitochondrial carriers with the focus on addressing the involvement of these carriers in human diseases.

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Structure of trypanosome coat protein VSGsur and function in suramin resistance

Cited by 25 publications

References 52 publications

Evolution of the variant surface glycoprotein family in African trypanosomes

Evolution of the variant surface glycoprotein family in African trypanosomes

The Glycosylphosphatidylinositol Anchor: A Linchpin for Cell Surface Versatility of Trypanosomatids

Learning from Yeast about Mitochondrial Carriers

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