Structure-based nuclear import mechanism of histones H3 and H4 mediated by Kap123.
Structure-based nuclear import mechanism of histones H3 and H4 mediated by Kap123.
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作者：
An S;Yoon J;Kim H;Song JJ;Cho US
Kap 123是芽殖酵母中的一种主要的核转运蛋白，它识别细胞质组蛋白H3和H4的核定位信号，并在DNA复制过程中将其转移到细胞核中。机制问题包括H3-和H4-NLS冗余对Kap 123和保守的细胞质H4（K5 ac和K12 ac）在Kap 123介导的组蛋白核转位的作用。在这里，我们报告晶体结构的全长乳酸克鲁维酵母Kap 123单独和复杂的H3和H4-NLS。结构揭示了Kap 123的独特特征，它具有两个用于NLS识别的离散的赖氨酸结合口袋。结构比较表明H3-和H4-NLS共享两个赖氨酸结合口袋中的至少一个，表明H3-和H4-NLS是相互排斥的。此外，NLS处关键赖氨酸残基的乙酰化，特别是H4-NLS二乙酰化，削弱了与Kap 123的相互作用。这些数据支持细胞质组蛋白H4双乙酰化减弱了Kap 123-H4-NLS相互作用，从而促进组蛋白Kap 123-H3依赖的H3：H4/Asf 1复合物核转位。
Kap123, a major karyopherin protein of budding yeast, recognizes the nuclear localization signals (NLSs) of cytoplasmic histones H3 and H4 and translocates them into the nucleus during DNA replication. Mechanistic questions include H3- and H4-NLS redundancy toward Kap123 and the role of the conserved diacetylation of cytoplasmic H4 (K5ac and K12ac) in Kap123-mediated histone nuclear translocation. Here, we report crystal structures of full-length Kluyveromyces lactis Kap123 alone and in complex with H3- and H4-NLSs. Structures reveal the unique feature of Kap123 that possesses two discrete lysine-binding pockets for NLS recognition. Structural comparison illustrates that H3- and H4-NLSs share at least one of two lysine-binding pockets, suggesting that H3- and H4-NLSs are mutually exclusive. Additionally, acetylation of key lysine residues at NLS, particularly H4-NLS diacetylation, weakens the interaction with Kap123. These data support that cytoplasmic histone H4 diacetylation weakens the Kap123-H4-NLS interaction thereby facilitating histone Kap123-H3-dependent H3:H4/Asf1 complex nuclear translocation.