scholarly journals Variable Surface Glycoprotein from Trypanosoma brucei Undergoes Cleavage by Matrix Metalloproteinases: An in silico Approach

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 178
Author(s):  
Cláudia Jassica Gonçalves Moreno ◽  
Taffarel Torres ◽  
Marcelo Sousa Silva
Keyword(s):  
Matrix Metalloproteinases ◽  
Trypanosoma Brucei ◽  
Cleavage Site ◽  
Surface Protein ◽  
Matrix Metalloproteases ◽  
Surface Glycoprotein ◽  
Mammalian Host ◽  
Variable Surface Glycoprotein ◽  
Biological Studies ◽  
Variable Surface

In order to survive as extracellular parasites in the mammalian host environment, Trypanosoma brucei has developed efficient mechanisms of immune system evasion, which include the abundant expression of a variable surface glycoprotein (VSG) coat. VSGs are anchored in the parasite membrane by covalent C-terminal binding to glycosylphosphatidylinositol and may be periodically removed by a phospholipase C (PLC) and a major surface protein (TbMSP). VSG molecules show extraordinary antigenic diversity and a comparative analysis of protein sequences suggests that conserved elements may be a suitable target against African trypanosomiasis. However, the cleavage mechanisms of these molecules remain unclear. Moreover, in protozoan infections, including those caused by Trypanosoma brucei, it is possible to observe an increased expression of the matrix metalloproteinases (MMPs). To address the cleavage mechanism of VSGs, the PROSPER server was used for the identification of VSG sequence cleavage sites. After data compilation, it was observed that 64 VSG consensus sequences showed a high conservation of hydrophobic residues, such as valine (V), methionine (M), leucine (L) and isoleucine (I) in the fifth position—the exact location of the cleavage site. In addition, the PROSPER server identified conserved cleavage site portions of VSG proteins recognized by three matrix metalloproteases (gelatinases: MMP-2, MMP-3 and MMP-9). However, further biological studies are needed in order to analyze and confirm this prediction.

scholarly journals Trypanosoma brucei Interaction with Host: Mechanism of VSG Release as Target for Drug Discovery for African Trypanosomiasis

2019 ◽  
Vol 20 (6) ◽  
pp. 1484 ◽  
Author(s):  
Cláudia Moreno ◽  
Adriana Temporão ◽  
Taffarel Torres ◽  
Marcelo Sousa Silva
Keyword(s):  
Drug Discovery ◽  
Phospholipase C ◽  
Trypanosoma Brucei ◽  
Antigenic Variation ◽  
Surface Glycoprotein ◽  
Mammalian Host ◽  
African Trypanosomiasis ◽  
Variable Surface Glycoprotein ◽  
Variable Surface ◽  
Major Surface

The protozoan Trypanosoma brucei, responsible for animal and human trypanosomiasis, has a family of major surface proteases (MSPs) and phospholipase-C (PLC), both involved in some mechanisms of virulence during mammalian infections. During parasitism in the mammalian host, this protozoan is exclusively extracellular and presents a robust mechanism of antigenic variation that allows the persistence of infection. There has been incredible progress in our understanding of how variable surface glycoproteins (VSGs) are organised and expressed, and how expression is switched, particularly through recombination. The objective of this manuscript is to create a reflection about the mechanisms of antigenic variation in T. brucei, more specifically, in the process of variable surface glycoprotein (VSG) release. We firstly explore the mechanism of VSG release as a potential pathway and target for the development of anti-T. brucei drugs.

Trypanosoma brucei: posttranscriptional control of the variable surface glycoprotein gene expression site

1989 ◽  
Vol 9 (9) ◽  
pp. 4018-4021
Author(s):  
E Pays ◽  
H Coquelet ◽  
A Pays ◽  
P Tebabi ◽  
M Steinert
Keyword(s):  
Gene Expression ◽  
Trypanosoma Brucei ◽  
Transcription Initiation ◽  
Tsetse Fly ◽  
Surface Glycoprotein ◽  
Insect Vector ◽  
Variable Surface Glycoprotein ◽  
A Genome ◽  
Variable Surface ◽  
Expression Site

The arrest of variable surface glycoprotein (VSG) synthesis is one of the first events accompanying the differentiation of Trypanosoma brucei bloodstream forms into procyclic forms, which are characteristic of the insect vector. This is because of a very fast inhibition of VSG gene transcription which occurs as soon as the temperature is lowered. We report that this effect is probably not controlled at the level of transcription initiation, since the beginning of the VSG gene expression site, about 45 kilobases upstream from the antigen gene, remains transcribed in procyclic forms. The permanent activity of the promoter readily accounts for the systematic reappearance, upon return to the bloodstream form after cyclical transmission, of the antigen type present before passage to the tsetse fly. The abortive transcription of the VSG gene expression site appears linked to RNA processing abnormalities. Such posttranscriptional controls may allow the modulation of gene expression in a genome organized in large multigenic transcription units.

Trypanosoma brucei: enrichment by UV of intergenic transcripts from the variable surface glycoprotein gene expression site

1989 ◽  
Vol 9 (9) ◽  
pp. 4022-4025
Author(s):  
H Coquelet ◽  
P Tebabi ◽  
A Pays ◽  
M Steinert ◽  
E Pays
Keyword(s):  
Gene Expression ◽  
Trypanosoma Brucei ◽  
Uv Irradiation ◽  
Surface Glycoprotein ◽  
Putative Promoter Region ◽  
Variable Surface Glycoprotein ◽  
Polycistronic Transcription ◽  
Variable Surface ◽  
Intergenic Regions ◽  
Expression Site

The expression site for the variable surface glycoprotein (VSG) gene AnTat 1.3A of Trypanosoma brucei is 45 kilobases long and encompasses seven expression site-associated genes (ESAGs) (E. Pays, P. Tebabi, A. Pays, H. Coquelet, P. Revelard, D. Salmon, and M. Steinert, Cell 57:835-845, 1989). After UV irradiation, several large transcripts from the putative promoter region were strongly enriched. We report that one such major transcript starts near the poly(A) addition site of the first gene (ESAG 7), spans the intergenic region, and extends to the poly(A) addition site of the second gene (ESAG 6), thus bypassing the normal 3' splice site of the ESAG 6 mRNA. Since this transcript is spliced, we conclude that UV irradiation does not inhibit splicing but stabilizes unstable processing products. This demonstrates that at least some intergenic regions of the VSG gene expression site are continuously transcribed in accordance with a polycistronic transcription model.

scholarly journals Subcellular localization of a variable surface glycoprotein phosphatidylinositol-specific phospholipase-C in African trypanosomes.

1987 ◽  
Vol 105 (2) ◽  
pp. 737-746 ◽  
Author(s):  
D J Grab ◽  
P Webster ◽  
S Ito ◽  
W R Fish ◽  
Y Verjee ◽  
...  
Keyword(s):  
Phospholipase C ◽  
Trypanosoma Brucei ◽  
Specific Activity ◽  
Surface Glycoprotein ◽  
Trypanosoma Vivax ◽  
Trypanosome Species ◽  
Phospholipase Activity ◽  
African Trypanosomes ◽  
Variable Surface Glycoprotein ◽  
Variable Surface

African trypanosomes contain a membrane-bound enzyme capable of removing dimyristylglycerol from the membrane-attached form of the variable surface glycoprotein (mfVSG; Ferguson, M. A. J., K. Halder, and G. A. M. Cross, 1985, J. Biol Chem., 260:4963-4968). Although mfVSG phospholipase-C has been implicated in the removal of the VSG from the trypanosome surface (Cardoso de Almeida, M. L., and M. J. Turner, 1983, Nature (Lond.)., 302:349-352; Ferguson, M. A. J., K. Halder, and G. A. M. Cross, 1985, J. Biol Chem., 260:4963-4968), its precise function and subcellular location have not been determined. We have developed a procedure for the separation of the cell fractions and organelles of Trypanosoma brucei brucei (and other trypanosome species) by differential sucrose and isopycnic PercollR centrifugation. These fractions were tested for mfVSG phospholipase activity using Trypanosoma brucei mfVSG labeled with 3H-myristic acid as substrate. The highest enzyme-specific activity was associated with the flagella and evidence is presented to suggest that it is localized in the flagellar pocket. Some activity was also associated with the Golgi complex. These results suggest that the mfVSG phospholipase is localized primarily in the membrane of the flagella pocket and possibly other membrane organelles derived from and associated with this structure, and may be part of the VSG-membrane recycling system in African trypanosomes. The activity of mfVSG phospholipase amongst various trypanosome species was determined. We show that, in contrast to the bloodstream forms of Trypanosoma brucei, cultured procyclic Trypanosoma brucei and bloodstream Trypanosoma vivax had little or no mfVSG phospholipase activity. The activity found in bloodstream forms of Trypanosoma congolense was intermediate between Trypanosoma vivax and Trypanosoma brucei.

scholarly journals Characterization of a transcription terminator of the procyclin PARP A unit of Trypanosoma brucei.

1996 ◽  
Vol 16 (3) ◽  
pp. 914-924 ◽  
Author(s):  
M Berberof ◽  
A Pays ◽  
S Lips ◽  
P Tebabi ◽  
E Pays
Keyword(s):  
Trypanosoma Brucei ◽  
Protein A ◽  
Surface Protein ◽  
Chloramphenicol Acetyltransferase ◽  
Transcription Unit ◽  
Open Reading Frames ◽  
Surface Glycoprotein ◽  
Transcription Terminator ◽  
Variable Surface

The polycistronic procylcin PARP (for procyclic acidic repetitive protein) A transcription unit of Trypanosoma brucei was completely characterized by the mapping of the termination region. In addition to the tandem of procyclin genes and GRESAG 2.1, this 7.5- to 9.5-kb unit contained another gene for a putative surface protein, termed PAG (for procyclin-associated gene) 3. The terminal 3-kb sequence did not contain significant open reading frames and cross-hybridized with the beginning of one or several transcription units specific to the bloodstream form. At least three separate fragments from the terminal region were able to inhibit chloramphenicol acetyltransferase expression when inserted between either the PARP, the ribosomal, or the variable surface glycoprotein promoter and a chloramphenicol acetyltransferase reporter gene. This inhibition was due to an orientation-dependent transcription termination caused by the combination of several attenuator elements with no obvious sequence conservation. The procyclin transcription terminator appeared unable to inhibit transcription by polymerase II.

scholarly journals Trypanosoma brucei: enrichment by UV of intergenic transcripts from the variable surface glycoprotein gene expression site.

1989 ◽  
Vol 9 (9) ◽  
pp. 4022-4025 ◽  
Author(s):  
H Coquelet ◽  
P Tebabi ◽  
A Pays ◽  
M Steinert ◽  
E Pays
Keyword(s):  
Gene Expression ◽  
Trypanosoma Brucei ◽  
Uv Irradiation ◽  
Surface Glycoprotein ◽  
Putative Promoter Region ◽  
Variable Surface Glycoprotein ◽  
Polycistronic Transcription ◽  
Variable Surface ◽  
Intergenic Regions ◽  
Expression Site

The expression site for the variable surface glycoprotein (VSG) gene AnTat 1.3A of Trypanosoma brucei is 45 kilobases long and encompasses seven expression site-associated genes (ESAGs) (E. Pays, P. Tebabi, A. Pays, H. Coquelet, P. Revelard, D. Salmon, and M. Steinert, Cell 57:835-845, 1989). After UV irradiation, several large transcripts from the putative promoter region were strongly enriched. We report that one such major transcript starts near the poly(A) addition site of the first gene (ESAG 7), spans the intergenic region, and extends to the poly(A) addition site of the second gene (ESAG 6), thus bypassing the normal 3' splice site of the ESAG 6 mRNA. Since this transcript is spliced, we conclude that UV irradiation does not inhibit splicing but stabilizes unstable processing products. This demonstrates that at least some intergenic regions of the VSG gene expression site are continuously transcribed in accordance with a polycistronic transcription model.

The 5′ flanking sequence of a Trypanosoma brucei variable surface glycoprotein gene

1987 ◽  
Vol 24 (2) ◽  
pp. 163-174 ◽  
Author(s):  
Jyotsna S. Shah ◽  
John R. Young ◽  
Bruce E. Kimmel ◽  
Keith P. Iams ◽  
Richard O. Williams
Keyword(s):  
Trypanosoma Brucei ◽  
Surface Glycoprotein ◽  
Flanking Sequence ◽  
Variable Surface Glycoprotein ◽  
Glycoprotein Gene ◽  
Variable Surface

scholarly journals Trypanosoma brucei: posttranscriptional control of the variable surface glycoprotein gene expression site.

1989 ◽  
Vol 9 (9) ◽  
pp. 4018-4021 ◽  
Author(s):  
E Pays ◽  
H Coquelet ◽  
A Pays ◽  
P Tebabi ◽  
M Steinert
Keyword(s):  
Gene Expression ◽  
Trypanosoma Brucei ◽  
Transcription Initiation ◽  
Tsetse Fly ◽  
Surface Glycoprotein ◽  
Insect Vector ◽  
Variable Surface Glycoprotein ◽  
A Genome ◽  
Variable Surface ◽  
Expression Site

The arrest of variable surface glycoprotein (VSG) synthesis is one of the first events accompanying the differentiation of Trypanosoma brucei bloodstream forms into procyclic forms, which are characteristic of the insect vector. This is because of a very fast inhibition of VSG gene transcription which occurs as soon as the temperature is lowered. We report that this effect is probably not controlled at the level of transcription initiation, since the beginning of the VSG gene expression site, about 45 kilobases upstream from the antigen gene, remains transcribed in procyclic forms. The permanent activity of the promoter readily accounts for the systematic reappearance, upon return to the bloodstream form after cyclical transmission, of the antigen type present before passage to the tsetse fly. The abortive transcription of the VSG gene expression site appears linked to RNA processing abnormalities. Such posttranscriptional controls may allow the modulation of gene expression in a genome organized in large multigenic transcription units.

6 Å-Resolution X-ray structure of a variable surface glycoprotein from Trypanosoma brucei

Nature ◽  
1984 ◽  
Vol 311 (5982) ◽  
pp. 167-169 ◽  
Author(s):  
D. M. Freymann ◽  
P. Metcalf ◽  
M. Turner ◽  
D. C. Wiley
Keyword(s):  
Trypanosoma Brucei ◽  
Surface Glycoprotein ◽  
X Ray ◽  
Variable Surface Glycoprotein ◽  
Variable Surface
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