The major histocompatibility complex class II (MHC II) membrane proteins are key players in the adaptive immune response. An aberrant function of these molecules is associated with a large number of autoimmune diseases such as diabetes type I and chronic inflammatory diseases. The MHC class II is assembled from DQ alpha 1 and DQ beta 1 which come together as a heterodimer through GXXXG-mediated protein-protein interactions and a highly specific protein-sphingomyelin-C18 interaction motif located on DQA1. This association can have important consequences in regulating the function of these membrane proteins. Here, we investigated the structure and topology of the DQA1 and DQB1 transmembrane helical domains by CD-, oriented 2H and 15N solid-state NMR spectroscopies. The spectra at peptide-to-lipid ratios of 0.5 to 2 mol% are indicative of a topological equilibrium involving a helix crossing the membrane with a tilt angle of about 20° and another transmembrane topology with around 30° tilt. The latter is probably representing a dimer. Furthermore, at the lowest peptide-to-lipid ratio, a third polypeptide population becomes obvious. Interestingly, the DQB1 and to a lesser extent the DQA1 transmembrane helical domains exhibit a strong fatty acyl chain disordering effect on the inner segments of the 2H-labelled palmitoyl chain of POPC bilayers. This phosphatidylcholine disordering requires the presence of sphingomyelin-C18 suggesting that the ensemble of transmembrane polypeptide and sphingolipid exerts positive curvature strain.

中文翻译：

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MHC II跨膜域的固态NMR研究：拓扑平衡和脂质相互作用。

主要的组织相容性复合物II类（MHC II）膜蛋白是适应性免疫反应的关键参与者。这些分子的异常功能与大量自身免疫性疾病如I型糖尿病和慢性炎性疾病有关。MHC II类由DQ alpha 1和DQ beta 1组装而成，它们通过GXXXG介导的蛋白质-蛋白质相互作用和位于DQA1上的高度特异性的蛋白质-鞘磷脂-C18相互作用基序，以异二聚体形式结合在一起。这种关联可能会在调节这些膜蛋白的功能中产生重要的后果。在这里，我们通过CD，取向的2H和15N固态NMR光谱学研究了DQA1和DQB1跨膜螺旋结构域的结构和拓扑。肽与脂质比率为0时的光谱。5至2mol％指示拓扑平衡，所述拓扑平衡包括螺旋以约20°的倾斜角穿过膜并且具有约30°的倾斜的另一跨膜拓扑。后者可能代表二聚体。此外，在最低的肽与脂质比率下，第三个多肽群体变得明显。有趣的是，DQB1和较小程度的DQA1跨膜螺旋结构域对POPC双层2H标记的棕榈酰基链的内部片段表现出很强的脂肪酰基链无序效应。这种磷脂酰胆碱失调需要鞘磷脂-C18的存在，这表明跨膜多肽和鞘脂的集合发挥正曲率应变。