Januliene Dovile, Manavalan Arulmani, Ovesen Peter Lund, Pedersen Karen-Marie, Thirup Søren, Nykjær Anders, Moeller Arne
Department of Structural Biology, Max Planck Institute of Biophysics, Max-von-Laue-Straße 3, 60438 Frankfurt am Main, Germany; DANDRITE, iNANO, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark.
Mayo Clinic, 4500 San Pablo Rd S, Jacksonville, FL 32224, USA.
J Mol Biol. 2017 Sep 15;429(19):2907-2917. doi: 10.1016/j.jmb.2017.08.006. Epub 2017 Aug 18.
SorCS1, SorCS2 and SorCS3 belong to the Vps10p-domain family of multiligand receptors. Genetic and functional studies have linked SorCS receptors to psychiatric disorders, Alzheimer's disease and type 2 diabetes, demonstrating critical roles in neuronal functionality and metabolic control. Surprisingly, their structural composition has so far not been studied. Here we have characterized SorCS1, SorCS2 and SorCS3 using biochemical methods and electron microscopy. We found that their purified extracellular domains co-exist in stable dimeric and monomeric populations. This was supported by co-immunoprecipitation experiments, where membrane-bound dimers were successfully pulled down from cell lysate. While dimers were virtually unbreakable, dimerization of the monomeric population was promoted through enzymatic deglycosylation. We conclude that post-translational modifications, specifically the degree and pattern of glycosylation, regulate the oligomeric state of the protein. Hence, cells may dictate ligand specificity by controlling the ratio between monomers and dimers and, therefore, regulate the multiple functions of SorCS receptors.
SorCS1、SorCS2和SorCS3属于多配体受体的Vps10p结构域家族。遗传学和功能研究已将SorCS受体与精神疾病、阿尔茨海默病和2型糖尿病联系起来，表明它们在神经元功能和代谢控制中起关键作用。令人惊讶的是，迄今为止尚未对它们的结构组成进行研究。在这里，我们使用生化方法和电子显微镜对SorCS1、SorCS2和SorCS3进行了表征。我们发现它们纯化的细胞外结构域以稳定的二聚体和单体形式共存。这得到了共免疫沉淀实验的支持，在该实验中，膜结合二聚体成功地从细胞裂解物中沉淀下来。虽然二聚体几乎不可断裂，但通过酶促去糖基化促进了单体群体的二聚化。我们得出结论，翻译后修饰，特别是糖基化的程度和模式，调节蛋白质的寡聚状态。因此，细胞可以通过控制单体和二聚体之间的比例来决定配体特异性，从而调节SorCS受体的多种功能。
