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Cryo-EM structure of a designed pyridoxal phosphate (PLP) synthase fused to a designed circumsporozoite protein antigen from Plasmodium falciparum (CSP-P1-CSP and CSP-P2-CSP)
Structural highlights
FunctionPDX2_PLAF7 Catalyzes the hydrolysis of glutamine to glutamate and ammonia as part of the biosynthesis of pyridoxal 5'-phosphate. The resulting ammonia molecule is channeled to the active site of Pdx1.[1] [2] CSP_PLAF7 Essential sporozoite protein (PubMed:29554084, PubMed:32150583). In the mosquito vector, required for sporozoite development in the oocyst, migration through the vector hemolymph and entry into the vector salivary glands (By similarity). In the vertebrate host, required for sporozoite migration through the host dermis and infection of host hepatocytes (PubMed:29554084, PubMed:32150583). Binds to highly sulfated heparan sulfate proteoglycans (HSPGs) on the surface of host hepatocytes (By similarity).[UniProtKB:P23093][3] [4] In the vertebrate host, binds to highly sulfated heparan sulfate proteoglycans (HSPGs) on the surface of host hepatocytes and is required for sporozoite invasion of the host hepatocytes.[UniProtKB:P23093] Publication Abstract from PubMedProtein nanoparticles in infectious disease vaccines enable protection through the periodic arrangement of antigens on their surface. These nanoparticles arise from organisms unrelated to the target disease, limiting their role as presentation platforms. Nanoparticles may also be compromised by pre-existing immunity to the nanoparticle carrier and may induce autoimmunity if conserved epitopes exist. Here we developed a potent multivalent malaria vaccine using an engineered Plasmodium falciparum pyridoxal 5'-phosphate (PLP) synthase as a nanoparticle that presents a designed P. falciparum circumsporozoite protein (CSP) and the Plasmodium vivax cell-transversal protein for ookinetes and sporozoites (CelTOS). These engineered vaccines elicited high titres of anti-CSP and anti-CelTOS antibodies, and three doses provided complete sterile protection against malaria in a mouse model. Cryogenic electron microscopy resolved a 2.95-A resolution structure of the PLP nanoparticle including amino acid changes engineered to stabilize the nanoparticle. PLP synthase has no identifiable human ortholog limiting its propensity for autoimmunity or pre-existing immunity, and the engineered nanoparticles possess desirable manufacturing characteristics. These studies established an effective nanoparticle platform for malaria and infectious disease vaccines. A Plasmodium-derived nanoparticle vaccine elicits sterile protection against malaria in mice.,Shi D, Ma R, Gupta R, Dickey TH, Patel PN, Salinas ND, Tang WK, Queen A, Singleton M, Delbe N, Conteh S, Lambert LE, Duffy PE, Tolia NH Nat Microbiol. 2025 Dec 19. doi: 10.1038/s41564-025-02209-y. PMID:41420060[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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