Yelland Tamas, Djordjevic Snezana
The Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK.
The Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK.
Structure. 2016 Nov 1;24(11):2008-2015. doi: 10.1016/j.str.2016.08.017. Epub 2016 Oct 6.
Neuropilins (NRPs) are single-pass transmembrane receptors involved in several signaling pathways that regulate key physiological processes such as vascular morphogenesis and axon guidance. The MAM domain of NRP, which has previously been implicated in receptor multimerization, was the only portion of the ectopic domain of the NRPs for which the structure, until now, has been elusive. Using site-directed mutagenesis in the linker region preceding the MAM domain we generated a protein construct amenable to crystallization. Here we present the crystal structure of the MAM domain of human NRP1 at 2.24 Å resolution. The protein exhibits a jellyroll topology, with Ca ions bound at the inter-strand space enhancing the thermostability of the domain. We show that the MAM domain of NRP1 is monomeric in solution and insufficient to drive receptor dimerization, which leads us to propose a different role for this domain in the context of NRP membrane assembly and signaling.
神经纤毛蛋白（NRPs）是单次跨膜受体，参与多种信号通路，这些信号通路调节诸如血管形态发生和轴突导向等关键生理过程。NRP的MAM结构域先前被认为与受体多聚化有关，它是NRPs胞外结构域中迄今为止结构仍不清楚的唯一部分。通过在MAM结构域之前的连接区进行定点诱变，我们构建了一种适合结晶的蛋白质。在此，我们展示了人NRP1的MAM结构域在2.24 Å分辨率下的晶体结构。该蛋白质呈现出果冻卷拓扑结构，钙离子结合在链间空间增强了结构域的热稳定性。我们表明，NRP1的MAM结构域在溶液中是单体形式，不足以驱动受体二聚化，这使我们在NRP膜组装和信号传导的背景下对该结构域提出了不同的作用。
