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Annexin A1 is regulated by domains cross-talk through post-translational phosphorylation and SUMOYlation

机译：Annexin A1通过翻译后磷酸化和SUMOYlation的结构域串扰调节

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摘要

Mouse prostate membrane-associated proteins of the annexin family showed changes in SUMOylation during androgen treatment. Among these the calcium-binding annexin A1 protein (ANXA1) was chosen for further characterization given its role in protein secretion and cancer. SUMOylation of ANXA1 was confirmed by overexpressing SUMO-1 in LNCaP cells. Site-directed mutagenesis indicated that K257 located in a SUMOylation consensus motif in the C-terminal calcium-binding DA3 repeat domain is SUMOylated. Mutation of the N-terminal Y21 decreased markedly the SUMOylation signal while EGF stimulation increased ANXA1 SUMOylation. A structural analysis of ANXA1 revealed that K257 is located in a hot spot where Ca~(2+) and SUMO-1 bind and where a nuclear export signal and a polyubiquitination site are also present. Also, Y21 is buried inside an α-helix structure in the Ca~(2+)-free conformation implying that Ca~(2+) binding, and the subsequent expelling of the N-terminal α-helix in a disordered conformation, is permissive for its phosphorylation. These results show for the first time that SUMOylation can be regulated by an external signal (EGF) and indicate the presence of a cross-talk between the N-terminal and C-terminal domains of ANXA1 through post-translational modifications.
机译：膜联蛋白家族的小鼠前列腺膜相关蛋白在雄激素治疗期间显示出SUMOylation的变化。考虑到钙结合膜联蛋白A1蛋白在蛋白质分泌和癌症中的作用，选择了钙结合膜联蛋白A1蛋白（ANXA1）作进一步表征。通过在LNCaP细胞中过表达SUMO-1来确认ANXA1的SUMO化。定点诱变表明，位于C末端钙结合DA3重复域中SUMOylation共有基序中的K257被SUMOylated。 N端Y21突变显着降低了SUMOylation信号，而EGF刺激增加了ANXA1 SUMOylation。 ANXA1的结构分析表明，K257位于Ca〜（2+）和SUMO-1结合的热点，并且还存在核输出信号和多聚泛素化位点。同样，Y21被埋没在无Ca〜（2+）构象的α螺旋结构内，这意味着Ca〜（2+）的结合以及随后无序构象的N末端α螺旋的排出是：允许其磷酸化。这些结果首次表明SUMOylation可以通过外部信号（EGF）进行调节，并表明ANXA1的N端和C端结构域之间通过翻译后修饰存在串扰。

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