Structural Biology Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 29 Lincoln Drive, Bethesda, MD, 20892, USA.
Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 29 Lincoln Drive, Bethesda, MD, 20892, USA.
Commun Biol. 2020 Jul 24;3(1):395. doi: 10.1038/s42003-020-01123-9.
Proteins Pfs230 and Pfs48/45 are Plasmodium falciparum transmission-blocking (TB) vaccine candidates that form a membrane-bound protein complex on gametes. The biological role of Pfs230 or the Pfs230-Pfs48/45 complex remains poorly understood. Here, we present the crystal structure of recombinant Pfs230 domain 1 (Pfs230D1M), a 6-cysteine domain, in complex with the Fab fragment of a TB monoclonal antibody (mAb) 4F12. We observed the arrangement of Pfs230 on the surface of macrogametes differed from that on microgametes, and that Pfs230, with no known membrane anchor, may exist on the membrane surface in the absence of Pfs48/45. 4F12 appears to sterically interfere with Pfs230 function. Combining mAbs against different epitopes of Pfs230D1 or of Pfs230D1 and Pfs48/45, significantly increased TB activity. These studies elucidate a mechanism of action of the Pfs230D1 vaccine, model the functional activity induced by a polyclonal antibody response and support the development of TB vaccines targeting Pfs230D1 and Pfs230D1-Pfs48/45.
蛋白 Pfs230 和 Pfs48/45 是恶性疟原虫传播阻断（TB）疫苗候选物，它们在配子上形成一个膜结合蛋白复合物。Pfs230 或 Pfs230-Pfs48/45 复合物的生物学作用仍知之甚少。在这里，我们展示了重组 Pfs230 结构域 1（Pfs230D1M）的晶体结构，这是一个 6 个半胱氨酸结构域，与 TB 单克隆抗体（mAb）4F12 的 Fab 片段复合物。我们观察到，在大配子表面上的 Pfs230 排列与在小配子表面上的排列不同，而且没有已知的膜锚定的 Pfs230 可能在没有 Pfs48/45 的情况下存在于膜表面上。4F12 似乎在空间上干扰 Pfs230 的功能。针对 Pfs230D1 的不同表位或 Pfs230D1 和 Pfs48/45 的 mAb 的结合，显著增加了 TB 活性。这些研究阐明了 Pfs230D1 疫苗的作用机制，模拟了多克隆抗体反应诱导的功能活性，并支持针对 Pfs230D1 和 Pfs230D1-Pfs48/45 的 TB 疫苗的开发。
