Meza-Romero Roberto, Benedek Gil, Leng Lin, Bucala Richard, Vandenbark Arthur A
Neuroimmunology Research, VA Portland Health Care System, 3710 SW US Veterans Hosp. Rd, Portland, OR, 97239, USA.
Tykeson MS Research Laboratory, Department of Neurology UHS-46, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, USA.
Metab Brain Dis. 2016 Apr;31(2):249-55. doi: 10.1007/s11011-016-9798-x. Epub 2016 Feb 6.
Macrophage migration inhibitory factor (MIF) is a key cytokine in autoimmune and inflammatory diseases that attracts and then retains activated immune cells from the periphery to the tissues. MIF exists as a homotrimer and its effects are mediated through its primary receptor, CD74 (the class II invariant chain that exhibits a highly structured trimerization domain), present on class II expressing cells. Although a number of binding residues have been identified between MIF and CD74 trimers, their spatial orientation has not been established. Using a docking program in silico, we have modeled binding interactions between CD74 and MIF as well as CD74 and a competitive MIF inhibitor, RTL1000, a partial MHC class II construct that is currently in clinical trials for multiple sclerosis. These analyses revealed 3 binding sites on the MIF trimer that each were predicted to bind one CD74 trimer through interactions with two distinct 5 amino acid determinants. Surprisingly, predicted binding of one CD74 trimer to a single RTL1000 antagonist utilized the same two 5 residue determinants, providing strong suggestive evidence in support of the MIF binding regions on CD74. Taken together, our structural modeling predicts a new MIF(CD74)3 dodecamer that may provide the basis for increased MIF potency and the requirement for ~3-fold excess RTL1000 to achieve full antagonism.
巨噬细胞移动抑制因子(MIF)是自身免疫性疾病和炎症性疾病中的一种关键细胞因子,它能吸引外周的活化免疫细胞并使其滞留于组织中。MIF以同三聚体形式存在,其作用通过其主要受体CD74(II类恒定链,具有高度结构化的三聚化结构域)介导,该受体存在于表达II类分子的细胞上。尽管已经确定了MIF与CD74三聚体之间的一些结合残基,但它们的空间取向尚未明确。我们利用计算机对接程序,对CD74与MIF以及CD74与一种竞争性MIF抑制剂RTL1000(一种部分MHC II类构建体,目前正处于多发性硬化症的临床试验阶段)之间的结合相互作用进行了建模。这些分析揭示了MIF三聚体上的3个结合位点,预计每个位点通过与两个不同的5个氨基酸决定簇相互作用结合一个CD74三聚体。令人惊讶的是,预测一个CD74三聚体与单个RTL1000拮抗剂的结合利用了相同的两个5个残基决定簇,为CD74上的MIF结合区域提供了有力的支持证据。综上所述,我们的结构建模预测了一种新的MIF(CD74)3十二聚体,它可能为提高MIF效力以及需要约3倍过量的RTL1000才能实现完全拮抗作用提供基础。