Structural insights into chondroitin sulfate binding in pregnancy-associated malaria

2010 ◽  
Vol 38 (5) ◽  
pp. 1337-1341 ◽  
Author(s):  
Pongsak Khunrae ◽  
Matthew K. Higgins
Keyword(s):  
Chondroitin Sulfate ◽  
Infected Erythrocyte ◽  
Binding Pocket ◽  
Chondroitin Sulfate Proteoglycans ◽  
Ligand Specificity ◽  
Erythrocyte Surface ◽  
Malaria During Pregnancy ◽  
Structural Insights ◽  
Major Target

Malaria during pregnancy is caused when parasite-infected erythrocytes accumulate within the placenta through interactions between the VAR2CSA protein on the infected erythrocyte surface and placental CSPGs (chondroitin sulfate proteoglycans). This interaction is the major target for therapeutics to treat or prevent pregnancy-associated malaria. Here we review the structural characterization of CSPG-binding DBL (Duffy-binding like) domains from VAR2CSA and summarize the growing evidence that the exquisite ligand specificity of VAR2CSA results from the adoption of higher-order architecture in which these domains fold together to form a ligand-binding pocket.

scholarly journals An affinity chromatography and glycoproteomics workflow to profile the chondroitin sulfate proteoglycans that interact with malarial VAR2CSA in the placenta and in cancer

Glycobiology ◽  
2020 ◽  
Vol 30 (12) ◽  
pp. 989-1002 ◽  
Author(s):  
Alejandro Gómez Toledo ◽  
Jessica Pihl ◽  
Charlotte B Spliid ◽  
Andrea Persson ◽  
Jonas Nilsson ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Affinity Purification ◽  
Chondroitin Sulfate Proteoglycans ◽  
Intervillous Space ◽  
Core Proteins ◽  
Heterogenous Group ◽  
Tumor Tissues ◽  
Infected Cells ◽  
Cancer Tissues

Abstract Chondroitin sulfate (CS) is the placental receptor for the VAR2CSA malaria protein, expressed at the surface of infected erythrocytes during Plasmodium falciparum infection. Infected cells adhere to syncytiotrophoblasts or get trapped within the intervillous space by binding to a determinant in a 4-O-sulfated CS chains. However, the exact structure of these glycan sequences remains unclear. VAR2CSA-reactive CS is also expressed by tumor cells, making it an attractive target for cancer diagnosis and therapeutics. The identities of the proteoglycans carrying these modifications in placental and cancer tissues remain poorly characterized. This information is clinically relevant since presentation of the glycan chains may be mediated by novel core proteins or by a limited subset of established proteoglycans. To address this question, VAR2CSA-binding proteoglycans were affinity-purified from the human placenta, tumor tissues and cancer cells and analyzed through a specialized glycoproteomics workflow. We show that VAR2CSA-reactive CS chains associate with a heterogenous group of proteoglycans, including novel core proteins. Additionally, this work demonstrates how affinity purification in combination with glycoproteomics analysis can facilitate the characterization of CSPGs with distinct CS epitopes. A similar workflow can be applied to investigate the interaction of CSPGs with other CS binding lectins as well.

Isolation and characterization of chondroitin sulfate proteoglycans from porcine thoracic aorta

1986 ◽  
Vol 883 (1) ◽  
pp. 83-90 ◽  
Author(s):  
Junichiro Aikawa ◽  
Mamoru Isemura ◽  
Hiroshi Munakata ◽  
Noboru Ototani ◽  
Chie Kodama ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Thoracic Aorta ◽  
Chondroitin Sulfate Proteoglycans ◽  
Isolation And Characterization

scholarly journals Structural insights into the recognition of mono- and di-acetylated histones by the ATAD2B bromodomain

2018 ◽  
Author(s):  
Jonathan T. Lloyd ◽  
Kyle McLaughlin ◽  
Mulu Y. Lubula ◽  
Jamie C. Gay ◽  
Andrea Dest ◽  
...  
Keyword(s):  
Binding Pocket ◽  
List Type ◽  
Lysine Acetylation ◽  
Ligand Specificity ◽  
Inhibitor Binding ◽  
Functional Relationships ◽  
Functional Features ◽  
Key Residues ◽  
Structural Insights ◽  
Alternate Splice Variant

ABSTRACTBromodomains are chromatin reader modules that recognize acetylated lysine. Different bromodomains exhibit a preference for specific patterns of lysine acetylation marks on core and variant histone proteins, however, the functional relationships that exist between histone acetyllysine ligands and bromodomain recognition remain poorly understood. In this study, we examined the ligand specificity of the ATAD2B bromodomain and compared it to its closely related paralog in ATAD2. We show that the ATAD2B bromodomain selects for mono- and di-acetylated histones, and structural analysis identified key residues in the acetyllysine binding pocket that dictate ligand binding specificity. The X-ray crystal structure of the ATAD2B bromodomain in complex with an ATAD2 bromodomain inhibitor was solved at 2.4 Å resolution. This structure demonstrated that critical contacts required for bromodomain inhibitor coordination are conserved between the ATAD2/B bromodomains, and many of these residues play a dual role in acetyllysine recognition. We further characterized a variant of the ATAD2B bromodomain that through alternative splicing loses critical amino acids required for histone ligand and inhibitor coordination. Altogether our results outline the structural and functional features of the ATAD2B bromodomain and identify a novel mechanism important for regulating the interaction of the ATAD2B protein with chromatin.HIGHLIGHTSThe ATAD2B bromodomain recognizes mono- and di-acetylated histone ligands.Chemical shift perturbations outline the ATAD2B bromodomain acetyllysine binding pocket.An ATAD2B bromodomain-inhibitor complex reveals important binding contacts.An alternate splice variant in the ATAD2B bromodomain abolishes histone and inhibitor binding.

scholarly journals Chondroitin Sulfate Proteoglycan Expression and Binding of Plasmodium falciparum-Infected Erythrocytes in the Human Placenta during Pregnancy

2003 ◽  
Vol 71 (5) ◽  
pp. 2455-2461 ◽  
Author(s):  
Sean T. Agbor-Enoh ◽  
Rajeshwara N. Achur ◽  
Manojkumar Valiyaveettil ◽  
Rose Leke ◽  
Diane W. Taylor ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Chondroitin Sulfate ◽  
Structural Changes ◽  
Gradual Increase ◽  
First Trimester ◽  
Chondroitin Sulfate Proteoglycans ◽  
Sulfate Content ◽  
Tissue Weight ◽  
Intervillous Space ◽  
Malaria During Pregnancy

ABSTRACT A characteristic feature of malaria during pregnancy is the sequestration of Plasmodium falciparum-infected red blood cells (IRBCs) in the intervillous spaces of the placenta. We have recently shown that unusually low-sulfated chondroitin sulfate proteoglycans (CSPGs) present in the intervillous spaces mediate the adherence of IRBCs in the placenta. In areas of endemicity, the prevalence of P. falciparum infection in pregnant women peaks during weeks 13 to 20 and then gradually declines, implying that the placental CSPGs are available for IRBC adhesion early during the pregnancy. However, there is no information on the expression and composition of CSPGs during pregnancy. In this study, the expression pattern of CSPGs during the course of pregnancy was investigated. The CSPGs were purified from placentas of various gestational ages, characterized, and tested for the ability to bind IRBCs. The data demonstrate that the CSPGs are present in the intervillous spaces throughout the second and third trimesters. The levels of CSPGs expressed per unit tissue weight were similar in placentas of various gestational ages. However, the structures of the intervillous-space CSPGs changed considerably during the course of pregnancy. In particular, the molecular weight was decreased, with an accompanying gradual increase in the CSPG size polydispersity, from 16 weeks until 38 weeks. The sulfate content was increased considerably after 24 weeks. Despite these structural changes, the CSPGs of placentas of various gestational ages efficiently supported the binding of IRBCs. These results demonstrate that CSPGs can mediate the sequestration of IRBCs in the intervillous spaces of the placenta during the entire second and third trimesters and possibly during the later part of the first trimester as well.

scholarly journals A Novel Chondroitin AC Lyase With Broad Substrate Specificity From Pedobacter rhizosphaerae: Cloning, Expression, and Characterization

2021 ◽  
Vol 9 ◽  
Author(s):  
Li-Jian Zhou ◽  
Li-Bin Guo ◽  
Wei Wei ◽  
Zhi-Xiang Lv ◽  
Ye-Wang Zhang
Keyword(s):  
Hyaluronic Acid ◽  
Chondroitin Sulfate ◽  
Storage Stability ◽  
Specific Activity ◽  
High Specific Activity ◽  
Binding Pocket ◽  
Low Molecular Weight ◽  
Sulfate Production ◽  
Chondroitin Ac Lyase

Chondroitin AC lyase (ChSaseAC) is one of the essential polysaccharides lyases in low molecular chondroitin sulfate production. In this work, a novel PrChSaseAC from Pedobacter rhizosphaerae was successfully cloned, expressed in Escherichia coli. After optimizing the induction, the recombinant PrChSaseAC could be expressed efficiently at 0.1 mM IPTG, 25°C, and 12 h induction. Then, it was purified with Ni-NTA affinity chromatography. The characterization of the purified PrChSaseAC showed that it had high specific activity and good storage stability, which would favor the production of low molecular weight chondroitin sulfate. It also displayed activity toward chondroitin sulfate C and hyaluronic acid. PrChSaseAC had the highest activity at pH 7.5, 37°C, 10 mM Ca2+, and 5 mg/ml of chondroitin sulfate A. Molecular docking of substrate and enzyme showed the interactions between the enzyme and substrate; it revealed that the enzyme showed high activity to CS-A and hyaluronic acid, but lower activity to CS-C attributed to the structure of the binding pocket. The high stability and specific activity of the enzyme will benefit the industrial production or clinical treatment.

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