Equipe Labellisee Ligue 2015, Department of Integrated Structural Biology, Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), INSERM U1258/CNRS UMR 7104/Universite de Strasbourg, Illkirch, France.
A.N. Bach Institute of Biochemistry, Federal Research Center of Biotechnology of the Russian Academy of Sciences, Moscow, Russia.
Nat Commun. 2021 Mar 15;12(1):1677. doi: 10.1038/s41467-021-21908-8.
The seven 14-3-3 isoforms are highly abundant human proteins encoded by similar yet distinct genes. 14-3-3 proteins recognize phosphorylated motifs within numerous human and viral proteins. Here, we analyze by X-ray crystallography, fluorescence polarization, mutagenesis and fusicoccin-mediated modulation the structural basis and druggability of 14-3-3 binding to four E6 oncoproteins of tumorigenic human papillomaviruses. 14-3-3 isoforms bind variant and mutated phospho-motifs of E6 and unrelated protein RSK1 with different affinities, albeit following an ordered affinity ranking with conserved relative K ratios. Remarkably, 14-3-3 isoforms obey the same hierarchy when binding to most of their established targets, as supported by literature and a recent human complexome map. This knowledge allows predicting proportions of 14-3-3 isoforms engaged with phosphoproteins in various tissues. Notwithstanding their individual functions, cellular concentrations of 14-3-3 may be collectively adjusted to buffer the strongest phosphorylation outbursts, explaining their expression variations in different tissues and tumors.
七种 14-3-3 同种型是高度丰富的人类蛋白，由相似但不同的基因编码。14-3-3 蛋白识别人类和病毒蛋白中许多磷酸化模体。在这里，我们通过 X 射线晶体学、荧光偏振、突变和 fusicoccin 介导的调制来分析 14-3-3 与四种致瘤性人乳头瘤病毒 E6 癌蛋白结合的结构基础和可药性。14-3-3 同种型以不同的亲和力结合 E6 和无关蛋白 RSK1 的变体和突变磷酸基序，但遵循有序的亲和力排序和保守的相对 K 比。值得注意的是，14-3-3 同种型在结合大多数已建立的靶标时也遵循相同的层次结构，这得到了文献和最近的人类复合物图谱的支持。这一知识允许预测在各种组织中与磷酸化蛋白结合的 14-3-3 同种型的比例。尽管它们具有各自的功能，但 14-3-3 的细胞浓度可能会集体调整以缓冲最强的磷酸化爆发，从而解释它们在不同组织和肿瘤中的表达变化。
