Department of Biochemistry & Molecular Biology and USylvester Braman Family Breast Cancer Institute, Leonard Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Arch Biochem Biophys. 2010 Feb 15;494(2):216-25. doi: 10.1016/j.abb.2009.12.011. Epub 2009 Dec 22.
Allostery has evolved as a form of local communication between interacting protein partners allowing them to quickly sense changes in their immediate vicinity in response to external cues. Herein, using isothermal titration calorimetry (ITC) in conjunction with circular dichroism (CD) and macromolecular modeling (MM), we show that the binding of Grb2 adaptor--a key signaling molecule involved in the activation of Ras GTPase--to its downstream partners Sos1 guanine nucleotide exchange factor and Gab1 docker is under tight allosteric regulation. Specifically, our findings reveal that the binding of one molecule of Sos1 to the nSH3 domain allosterically induces a conformational change within Grb2 such that the loading of a second molecule of Sos1 onto the cSH3 domain is blocked and, in so doing, allows Gab1 access to the cSH3 domain in an exclusively non-competitive manner to generate the Sos1-Grb2-Gab1 ternary signaling complex.
变构作用已经进化为相互作用的蛋白质伴侣之间的一种局部通讯形式，使它们能够快速感知其周围环境的变化，以响应外部信号。在这里，我们使用等温滴定量热法（ITC）结合圆二色性（CD）和大分子建模（MM），表明 Grb2 衔接子 - 一种参与 Ras GTPase 激活的关键信号分子 - 与其下游伙伴 Sos1 鸟嘌呤核苷酸交换因子和 Gab1 衔接蛋白的结合受到严格的变构调节。具体而言，我们的发现表明，一个 Sos1 分子与 nSH3 结构域的结合变构诱导 Grb2 内的构象变化，使得第二个 Sos1 分子加载到 cSH3 结构域被阻断，并且，这样，允许 Gab1 以排他性非竞争方式进入 cSH3 结构域，以生成 Sos1-Grb2-Gab1 三元信号复合物。
