Structures of the PKA RIα Holoenzyme with the FLHCC Driver J-PKAcα or Wild-Type PKAcα
Structures of the PKA RIα Holoenzyme with the FLHCC Driver J-PKAcα or Wild-Type PKAcα
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DOI：
10.1016/j.str.2019.03.001
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发表时间：
2019-05-07
期刊：
影响因子：
5.7
通讯作者：
Zhang, Ping
中科院分区：
文献类型：
--
作者：
Cao, Baohua;Lu, Tsan-Wen;Zhang, Ping
纤维板层状肝细胞癌是由DNAJB1的J结构域与蛋白激酶A的催化亚单位PKAcα的融合蛋白J-PKAcα所驱动。在这里，我们报道了嵌合融合RIα(2)的晶体结构：J-PKAcα与PKA调节(R)亚单位RIα形成的J-PKAcα(2)全酶，以及野生型(WT)RIα(2)：PKAcα(2)全酶。嵌合和WT RIα全酶具有不同于先前解决的WT RIβ和RIIβ全酶的四级结构。WTRIα全酶与嵌合RIα(2)具有相同的构型：J-PKAcα(2)全酶和明显的第二构象。在嵌合融合全酶中，J结构域远离两个RIα：J-PKAcα异二聚体之间的对称界面，并且是高度动态的。这些全酶的结构和动态特征加深了我们对推动肝癌的融合嵌合体蛋白J-PKAcα以及PKA的异构体特异性的理解。
Fibrolamellar hepatocellular carcinoma (FLHCC) is driven by J-PKAc alpha, a kinase fusion chimera of the J domain of DnaJB1 with PKAc alpha, the catalytic subunit of protein kinase A (PKA). Here we report the crystal structures of the chimeric fusion RI alpha(2):J-PKAc alpha(2) holoenzyme formed by J-PKAc alpha and the PKA regulatory (R) subunit RI alpha, and the wild-type (WT) RI alpha(2):PKAc alpha(2) holoenzyme. The chimeric and WT RI alpha holoenzymes have quaternary structures different from the previously solved WT RI beta and RII beta holoenzymes. The WT RI alpha holoenzyme showed the same configuration as the chimeric RI alpha(2):J-PKAc alpha(2) holoenzyme and a distinct second conformation. The J domains are positioned away from the symmetrical interface between the two RI alpha:J-PKAc alpha heterodimers in the chimeric fusion holoenzyme and are highly dynamic. The structural and dynamic features of these holoenzymes enhance our understanding of the fusion chimera protein J-PKAc alpha that drives FLHCC as well as the isoform specificity of PKA.