The APPL (adaptor proteins containing pleckstrin homology domain, phosphotyrosine binding domain and a leucine zipper motif) family consists of two isoforms, APPL1 and APPL2. By binding to curved plasma membrane, these adaptor proteins associate with multiple transmembrane receptors and recruit various downstream signaling components. They are involved in the regulation of signaling pathways evoked by a variety of extracellular stimuli, such as adiponectin, insulin, FSH (follicle stimulating hormone), EGF (epidermal growth factor). And they play important roles in cell proliferation, apoptosis, glucose uptake, insulin secretion and sensitivity. However, emerging evidence suggests that APPL1 and APPL2 perform different or even opposite functions and the underlying mechanism remains unclear. As APPL proteins can either homodimerize or heterodimerize in vivo, we hypothesized that heterodimerization of APPL proteins might account for the mechanism. By solving the crystal structure of APPL1–APPL2 BAR-PH heterodimer, we find that the overall structure is crescent-shaped with a longer curvature radius of 76 Å, compared with 55 Å of the APPL1 BAR-PH homodimer. However, there is no significant difference of the curvature between APPL BAR-PH heterodimer and APPL2 homodimer. The data suggest that the APPL1 BAR-PH homodimer, APPL2 BAR-PH homodimer and APPL1/APPL2 BAR-PH heterodimer may bind to endosomes of different sizes. Different positive charge distribution is observed on the concave surface of APPL BAR-PH heterodimer than the homodimers, which may change the affinity of membrane association and subcellular localization. Collectively, APPL2 may regulate APPL1 function through altering the preference of endosome binding by heterodimerization.

中文翻译：

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人APPL BAR-PH异二聚体的晶体结构揭示了灵活的二聚体BAR曲线：内体靶向相互调节的意义


APPL（含有 pleckstrin 同源结构域、磷酸酪氨酸结合结构域和亮氨酸拉链基序的接头蛋白）家族由两种同工型 APPL1 和 APPL2 组成。通过与弯曲的质膜结合，这些衔接蛋白与多个跨膜受体结合并招募各种下游信号成分。它们参与多种细胞外刺激引起的信号通路的调节，如脂联素、胰岛素、FSH（卵泡刺激素）、EGF（表皮生长因子）。它们在细胞增殖、凋亡、葡萄糖摄取、胰岛素分泌和敏感性中发挥着重要作用。然而，新的证据表明APPL1和APPL2执行不同甚至相反的功能，并且潜在的机制仍不清楚。由于 APPL 蛋白在体内可以同二聚化或异二聚化，我们假设 APPL 蛋白的异二聚化可能解释了这一机制。通过解析APPL1–APPL2 BAR-PH异二聚体的晶体结构，我们发现整体结构呈新月形，曲率半径更长，为76 Å，而APPL1 BAR-PH同二聚体的曲率半径为55 Å。然而，APPL BAR-PH异二聚体和APPL2同二聚体之间的曲率没有显着差异。数据表明APPL1 BAR-PH同二聚体、APPL2 BAR-PH同二聚体和APPL1/APPL2 BAR-PH异二聚体可能与不同大小的内体结合。在APPL BAR-PH异二聚体的凹面上观察到与同二聚体不同的正电荷分布，这可能改变膜缔合和亚细胞定位的亲和力。总的来说，APPL2 可能通过异二聚化改变内体结合的偏好来调节 APPL1 功能。