Force spectroscopy of the Plasmodium falciparum vaccine candidate circumsporozoite protein suggests a mechanically pliable repeat region [Molecular Bases of Disease]

The most effective vaccine candidate of malaria is based on the Plasmodium falciparum circumsporozoite protein (CSP), a major surface protein implicated in the structural strength, motility and immune evasion properties of the infective sporozoites. It is suspected that reversible conformational changes of CSP are required for infection of the mammalian host, but CSP′s detailed structure and dynamic properties remain incompletely understood, limiting our understanding of its function in the infection. Here, we report the structural and mechanical properties of the CSP studied using single-molecule force spectroscopy on several constructs, one including CSP′s central region rich in NANP amino acid repeats (CSPrep) and a second consisting of a near full-length sequence without the signal and anchor hydrophobic domains (CSPΔHP). Our results show that the CSPrep is heterogeneous, with 40% molecules requiring virtually no mechanical force to unfold (<10 pN), suggesting these molecules are mechanically compliant and perhaps act as entropic springs, while the remaining 60% are partially structured with low mechanical resistance (~70 pN). CSPΔHP having multiple force peaks suggests specifically folded domains, with two major populations possibly indicating the open and collapsed forms. Our findings suggest that the overall low mechanical resistance of the repeat region, exposed on the outer surface of the sporozoites, combined with flexible full-length conformations of CSP, may provide the sporozoites not only with immune evasion properties, but also with lubricating capacity required during its navigation through the mosquito and vertebrate host tissues. We anticipate these findings would further assist in the design and development of future malarial vaccines.

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