Chan Jia Jia, Flatters Delphine, Rodrigues-Lima Fernando, Yan Jun, Thalassinos Konstantinos, Katan Matilda
Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK.
Adv Biol Regul. 2013 May;53(2):190-201. doi: 10.1016/j.jbior.2012.12.001. Epub 2013 Jan 11.
Members of the RASSF family (RASSF1-10) have been identified as candidate tumour suppressors that are frequently downregulated by promoter hypermethylation in cancers. These proteins carry a common Ras-association (RA) and SARAH domain (RASSF1-6) that can potentially bind Ras oncoproteins and mediate protein-protein interactions with other SARAH domain proteins. However, there is a notable lack of comparative characterisation of the RASSF family, as well as molecular and structural information that facilitate their tumour suppressive functions. As part of our comparative analysis, we modelled the RA and SARAH domains of the RASSF members based on existing structures and predicted their potential interactions. These in silico predictions were compared to in vitro interaction studies with Ras and MST kinase (a SARAH domain-containing protein). Our data shows a diversity of interaction within the RASSF family RA domain, whereas the SARAH domain-mediated interactions for RASSF1-6 are consistent with the predictions. This suggests that different members, despite shared general architecture, could have distinct functional properties. Additionally, we identify a new interacting partner for MST kinase in the form of RASSF7. Current data supports an interaction model where RASSF serves as an adaptor for the assembly of multiple protein complexes and further functional interactions, involving MST kinases and other SARAH domain proteins, which could be regulated by Ras.
RASSF家族成员（RASSF1 - 10）已被确定为候选肿瘤抑制因子，在癌症中它们常因启动子高甲基化而下调。这些蛋白质带有一个共同的Ras关联（RA）和SARAH结构域（RASSF1 - 6），该结构域可能与Ras癌蛋白结合，并介导与其他含SARAH结构域蛋白的蛋白质 - 蛋白质相互作用。然而，目前明显缺乏对RASSF家族的比较特征描述，以及有助于其肿瘤抑制功能的分子和结构信息。作为我们比较分析的一部分，我们基于现有结构对RASSF成员的RA和SARAH结构域进行建模，并预测它们的潜在相互作用。将这些计算机模拟预测结果与Ras和MST激酶（一种含SARAH结构域的蛋白质）的体外相互作用研究进行比较。我们的数据显示RASSF家族RA结构域内存在多种相互作用，而RASSF1 - 6的SARAH结构域介导的相互作用与预测结果一致。这表明不同成员尽管具有共同的总体结构，但可能具有不同的功能特性。此外，我们确定了RASSF7形式的MST激酶新相互作用伙伴。目前的数据支持一种相互作用模型，即RASSF作为多种蛋白质复合物组装和进一步功能相互作用的衔接子，涉及MST激酶和其他含SARAH结构域蛋白质，这些相互作用可能受Ras调控。
