Das Sreedam C, Morales Rodrigo A V, Seow Jeffrey, Krishnarjuna Bankala, Dissanayake Ravindu, Anders Robin F, MacRaild Christopher A, Norton Raymond S
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
FEBS J. 2017 Aug;284(16):2649-2662. doi: 10.1111/febs.14135. Epub 2017 Jul 5.
Merozoite surface protein 2 (MSP2) is a highly abundant, GPI-anchored antigen on the malaria parasite Plasmodium falciparum. MSP2 induces an immune response in the context of natural infections and vaccine trials, and these responses are associated with protection from parasite infection. Recombinant MSP2 is highly disordered in solution but antigenic analyses suggest that it is more ordered on the merozoite surface. We have shown previously that the interaction of recombinant full-length MSP2 with lipid surfaces induces a conformational change in the conserved N-terminal region of MSP2, which contributes to epitope masking in this region. To explore the impacts of lipid interactions on the conformation and antigenicity of the conserved C-terminal region of MSP2, a construct corresponding to this domain, MSP2 , was designed. NMR studies indicate that many residues in MSP2 interact with DPC micelles, including some in epitopes recognised by C-terminal-specific monoclonal antibodies, but, in contrast to the MSP2 N-terminus, there is no indication of stable helical conformation. The binding affinities of a panel of monoclonal antibodies indicate that MSP2 is antigenically similar to full-length MSP2 and show that liposome conjugation alters the antigenicity in a manner that may mimic native MSP2 on the merozoite surface. These findings highlight the impact of lipid interactions on the conformation and antigenicity of MSP2 and will assist in the design of recombinant MSP2 immunogens for use as malaria vaccine candidates.
Resonance assignments are available in the BioMagResBank (BMRB) database under the accession number 27134.
裂殖子表面蛋白2（MSP2）是恶性疟原虫上一种高度丰富的糖基磷脂酰肌醇锚定抗原。在自然感染和疫苗试验中，MSP2可诱导免疫反应，且这些反应与预防寄生虫感染相关。重组MSP2在溶液中高度无序，但抗原分析表明它在裂殖子表面更有序。我们之前已经表明，重组全长MSP2与脂质表面的相互作用会在MSP2保守的N端区域诱导构象变化，这有助于该区域的表位掩盖。为了探究脂质相互作用对MSP2保守C端区域的构象和抗原性的影响，设计了一个对应于该结构域的构建体MSP2 。核磁共振研究表明，MSP2中的许多残基与二棕榈酰磷脂酰胆碱（DPC）胶束相互作用，包括一些被C端特异性单克隆抗体识别的表位中的残基，但与MSP2的N端不同，没有迹象表明存在稳定的螺旋构象。一组单克隆抗体的结合亲和力表明，MSP2在抗原性上与全长MSP2相似，并表明脂质体偶联以一种可能模拟裂殖子表面天然MSP2的方式改变了抗原性。这些发现突出了脂质相互作用对MSP2构象和抗原性的影响，并将有助于设计用作疟疾疫苗候选物的重组MSP2免疫原。
共振归属可在生物磁共振银行（BMRB）数据库中获取，登录号为27134。
