PDF(Pubmed)
Abstract：
Salivary proteins from mosquitoes have received significant attention lately due to their potential to develop therapeutic treatments or vaccines for mosquito-borne diseases. Here, we report the characterization of LTRIN (lymphotoxin beta receptor inhibitor), a salivary protein known to enhance the pathogenicity of ZIKV by interrupting the LTβR-initiated NF-κB signaling pathway and, therefore, diminish the immune responses. We demonstrated that the truncated C-terminal LTRIN (ΔLTRIN) is a dimeric protein with a stable alpha helix-dominant secondary structure, which possibly aids in withstanding the temperature fluctuations during blood-feeding events. ΔLTRIN possesses two Ca2+ binding EF-hand domains, with the second EF-hand motif playing a more significant role in interacting with LTβR. Additionally, we mapped the primary binding regions of ΔLTRIN on LTβR using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and identified that 91QEKAHIAEHMDVPIDTSKMSEQELQFHY118 from the N-terminal of ΔLTRIN is the major interacting region. Together, our studies provide insight into the recognition of LTRIN by LTβR. This finding may aid in a future therapeutic and transmission-blocking vaccine development against ZIKV.
摘要：
来自蚊子的唾液蛋白由于其开发针对蚊子传播疾病的治疗性治疗或疫苗的潜力而最近受到了极大的关注。这里,我们报道了LTRIN（淋巴毒素β受体抑制剂）的特征，一种已知通过中断LTβR启动的NF-κB信号通路来增强ZIKV致病性的唾液蛋白,因此,减少免疫反应。我们证明了截短的C端LTRIN（ΔLTRIN）是具有稳定的α螺旋显性二级结构的二聚体蛋白，这可能有助于在血液喂养事件期间承受温度波动。ΔLTRIN具有两个Ca2结合EF-手结构域，第二EF手基序在与LTβR的相互作用中起着更重要的作用。此外,我们使用氢-氘交换质谱（HDX-MS）将ΔLTRIN的主要结合区域映射到LTβR上，并确定ΔLTRINN端的91QEKAHIAEHMDVPIDTSKMSEQELQFHY118是主要的相互作用区域。一起,我们的研究提供了对LTR识别LTRIN的见解。这一发现可能有助于未来针对ZIKV的治疗和传播阻断疫苗的开发。
