Zeng W, Xu X, Popov S, Mukhopadhyay S, Chidiac P, Swistok J, Danho W, Yagaloff K A, Fisher S L, Ross E M, Muallem S, Wilkie T M
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
J Biol Chem. 1998 Dec 25;273(52):34687-90. doi: 10.1074/jbc.273.52.34687.
Regulators of heterotrimeric G protein signaling (RGS) proteins are GTPase-activating proteins (GAPs) that accelerate GTP hydrolysis by Gq and Gi alpha subunits, thus attenuating signaling. Mechanisms that provide more precise regulatory specificity have been elusive. We report here that an N-terminal domain of RGS4 discriminated among receptor signaling complexes coupled via Gq. Accordingly, deletion of the N-terminal domain of RGS4 eliminated receptor selectivity and reduced potency by 10(4)-fold. Receptor selectivity and potency of inhibition were partially restored when the RGS4 box was added together with an N-terminal peptide. In vitro reconstitution experiments also indicated that sequences flanking the RGS4 box were essential for high potency GAP activity. Thus, RGS4 regulates Gq class signaling by the combined action of two domains: 1) the RGS box accelerates GTP hydrolysis by Galphaq and 2) the N terminus conveys high affinity and receptor-selective inhibition. These activities are each required for receptor selectivity and high potency inhibition of receptor-coupled Gq signaling.
异源三聚体G蛋白信号调节（RGS）蛋白是GTP酶激活蛋白（GAPs），可加速Gq和Giα亚基的GTP水解，从而减弱信号传导。提供更精确调节特异性的机制一直难以捉摸。我们在此报告，RGS4的N端结构域可区分通过Gq偶联的受体信号复合物。因此，缺失RGS4的N端结构域消除了受体选择性，并使效力降低了10^4倍。当RGS4结构域与N端肽一起添加时，受体选择性和抑制效力部分恢复。体外重组实验还表明，RGS4结构域两侧的序列对于高效GAP活性至关重要。因此，RGS4通过两个结构域的联合作用调节Gq类信号传导：1）RGS结构域加速Gαq的GTP水解；2）N端传递高亲和力和受体选择性抑制。这些活性对于受体选择性和高效抑制受体偶联的Gq信号传导均是必需的。
