Slater Paula G, Gutierrez-Maldonado Sebastian E, Gysling Katia, Lagos Carlos F
Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
Computational Biology Laboratory (DLab), Fundación Ciencia & Vida, Santiago, Chile.
Front Endocrinol (Lausanne). 2018 Feb 20;9:43. doi: 10.3389/fendo.2018.00043. eCollection 2018.
The corticotropin-releasing factor (CRF) system is a key mediator of the stress response and addictive behavior. The CRF system includes four peptides: The CRF system includes four peptides: CRF, urocortins I-III, CRF binding protein (CRF-BP) that binds CRF with high affinity, and two class B G-protein coupled receptors CRFR and CRFR. CRF-BP is a secreted protein without significant sequence homology to CRF receptors or to any other known class of protein. Recently, it has been described a potentiation role of CRF-BP over CRF signaling through CRFR in addictive-related neuronal plasticity and behavior. In addition, it has been described that CRF-BP is capable to physically interact specifically with the α isoform of CRFR and acts like an escort protein increasing the amount of the receptor in the plasma membrane. At present, there are no available structures for CRF-BP or for full-length CRFR. Knowing and studying the structure of these proteins could be beneficial in order to characterize the CRF-BP/CRFR interaction. In this work, we report the modeling of CRF-BP and of full-length CRFR and CRFR based on the recently solved crystal structures of the transmembrane domains of the human glucagon receptor and human CRFR, in addition with the resolved N-terminal extracellular domain of CRFRs. These models were further studied using molecular dynamics simulations and protein-protein docking. The results predicted a higher possibility of interaction of CRF-BP with CRFR than CRFR and yielded the possible residues conforming the interacting interface. Thus, the present study provides a framework for further investigation of the CRF-BP/CRFR interaction.
促肾上腺皮质激素释放因子（CRF）系统是应激反应和成瘾行为的关键调节因子。CRF系统包括四种肽：CRF、尿皮质素I-III、能与CRF高亲和力结合的CRF结合蛋白（CRF-BP），以及两种B类G蛋白偶联受体CRFR1和CRFR2。CRF-BP是一种分泌蛋白，与CRF受体或任何其他已知类别的蛋白质没有明显的序列同源性。最近，已有研究描述了CRF-BP在成瘾相关神经元可塑性和行为中通过CRFR1对CRF信号传导的增强作用。此外，已有研究表明CRF-BP能够与CRFR1的α亚型发生特异性物理相互作用，并像一种护送蛋白一样增加质膜中受体的数量。目前，尚无CRF-BP或全长CRFR的可用结构。了解和研究这些蛋白质的结构可能有助于表征CRF-BP/CRFR的相互作用。在这项工作中，我们基于最近解析的人胰高血糖素受体和人CRFR1的跨膜结构域的晶体结构，以及解析的CRFRs的N端细胞外结构域，报道了CRF-BP以及全长CRFR1和CRFR2的建模。这些模型通过分子动力学模拟和蛋白质-蛋白质对接进行了进一步研究。结果预测CRF-BP与CRFR1相互作用的可能性高于与CRFR2，并产生了构成相互作用界面的可能残基。因此，本研究为进一步研究CRF-BP/CRFR的相互作用提供了一个框架。
