Boskovic Jasminka, Arnold James N, Stilion Richard, Gordon Siamon, Sim Robert B, Rivera-Calzada Angel, Wienke Dirk, Isacke Clare M, Martinez-Pomares Luisa, Llorca Oscar
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu, 9, Campus Universidad Complutense, 28040 Madrid, Spain.
J Biol Chem. 2006 Mar 31;281(13):8780-7. doi: 10.1074/jbc.M513277200. Epub 2006 Feb 1.
The mannose receptor family comprises four members in mammals, Endo180 (CD280), DEC-205 (CD205), phospholipase A(2) receptor (PLA(2)R) and the mannose receptor (MR, CD206), whose extracellular portion contains a similar domain arrangement: an N-terminal cysteine-rich domain (CysR) followed by a single fibronectin type II domain (FNII) and 8-10 C-type lectin-like domains (CTLDs). These proteins mediate diverse functions ranging from extracellular matrix turnover through collagen uptake to homeostasis and immunity based on sugar recognition. Endo180 and the MR are multivalent transmembrane receptors capable of interacting with multiple ligands; in both receptors FNII recognizes collagens, and a single CTLD retains lectin activity (CTLD2 in Endo180 and CTLD4 in MR). It is expected that the overall conformation of these multivalent molecules would deeply influence their function as the availability of their binding sites could be altered under different conditions. However, conflicting reports have been published on the three-dimensional arrangement of these receptors. Here, we have used single particle electron microscopy to elucidate the three-dimensional organization of the MR and Endo180. Strikingly, we have found that both receptors display distinct three-dimensional structures, which are, however, conceptually very similar: a bent and compact conformation built upon interactions of the CysR domain and the lone functional CTLD. Biochemical and electron microscopy experiments indicate that, under a low pH mimicking the endosomal environment, both MR and Endo180 experience large conformational changes. We propose a structural model for the mannose receptor family where at least two conformations exist that may serve to regulate differences in ligand selectivity.
甘露糖受体家族在哺乳动物中包含四个成员，即Endo180（CD280）、DEC-205（CD205）、磷脂酶A2受体（PLA2R）和甘露糖受体（MR，CD206），它们的细胞外部分具有相似的结构域排列：一个N端富含半胱氨酸的结构域（CysR），接着是一个单纤维连接蛋白II型结构域（FNII）和8-10个C型凝集素样结构域（CTLD）。这些蛋白质介导多种功能，从通过胶原摄取进行细胞外基质周转到基于糖识别的稳态和免疫。Endo180和MR是能够与多种配体相互作用的多价跨膜受体；在这两种受体中，FNII识别胶原蛋白，单个CTLD保留凝集素活性（Endo180中的CTLD2和MR中的CTLD4）。预计这些多价分子的整体构象会深刻影响其功能，因为在不同条件下其结合位点的可用性可能会改变。然而，关于这些受体的三维排列已经发表了相互矛盾的报道。在这里，我们使用单颗粒电子显微镜来阐明MR和Endo180的三维结构。令人惊讶的是，我们发现这两种受体都呈现出独特的三维结构，然而，在概念上非常相似：一种基于CysR结构域和单个功能性CTLD相互作用构建的弯曲且紧凑的构象。生化和电子显微镜实验表明，在模拟内体环境的低pH条件下，MR和Endo180都会经历大的构象变化。我们提出了一个甘露糖受体家族的结构模型，其中至少存在两种构象，可能用于调节配体选择性的差异。
