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Title
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Investigating the role of intrinsic disorder in the structure-function relationship of the circumsporozoite protein from the malaria parasite
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Author
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Abstract
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| Malaria is a vector-born disease that poses a global health threat to almost half of the world's population. Annually, about 250 million cases over 600 thousand deaths are reported worldwide. The most afflicted region is Sub-Saharan-Africa, and children under the age of five form the most vulnerable group of the population. This devastating disease is caused by parasites belong to the Plasmodium genus, which are injected in their sporozoite (SPZ) life form into the skin of the human host during blood feeding of an infected female Anopheles mosquito. From there, they travel to the liver and differentiate into tens of thousands of merozoites, which later on re-occur in the circulation to asexually replicate within erythrocytes and cause the notorious malaria pathology. The circumsporozoite protein (CSP) is the SPZ’s main surface antigen, which uniformly coats its surface and plays a pivotal role in its immunobiology, both in the insect and the human hosts. In addition, it constitutes the immunodominant target for host antibodies raised against the SPZ life stage, and therefore forms the basis of the only two WHO-approved malaria vaccines today. CSP has a conserved modular buildup consisting of: i) an N-terminal domain (CSPN); ii) a linker region composed of tandem repeats (CSPrep); iii) a C-terminal domain (CSPC) that consist of a flexible junctional region that connects the globular part of the domain (αTSR domain) to CSPrep; and iv) a C-terminal GPI anchor attaching the antigen to the SPZ plasma membrane. Despite significant advances made during the past decades and the clear relevance of CSP in SPZ immunobiology, the structures of full-length CSP (CSPFL) and CSPN, and most aspects of its structure-function relationship, remain enigmatic. The research focus of this doctorate was to investigate the role of intrinsic disorder in the structure-function relationship of CSP, with particular attention devoted to CSP from P. falciparum (PfaCSP) and P. vivax (PviCSP) as the most dominant human-infective species, and P. berghei (PbeCSP) as a commonly used model system. Several constructs corresponding to CSPFL or truncates thereof were recombinantly produced and purified. Subsequently, an interdisciplinary approach was used to characterize CSPN and CSPFL as intrinsically disordered regions and proteins, respectively. In addition, we present the first all-atom conformational ensemble of PfaCSP and validate that the surface antigen is subject to a conformation change during SPZ development in the mosquito. Finally, the molecular details of two CSP-mediated ligand interactions that play important roles in parasite biology were investigated. |
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Language
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English
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Publication
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Antwerp
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University of Antwerp & Vrije Universiteit Brussel
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2024
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DOI
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10.63028/10067/2052560151162165141
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Volume/pages
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XXI, 328 p.
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Note
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Sterckx, Yann [Supervisor]
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Tompa, Peter [Supervisor]
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Volkov, Oleksandr [Supervisor]
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Full text (open access)
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The publisher created published version Available from 19.04.2026
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