Sequence Determinants of the Conformational Properties of an Intrinsically Disordered Protein Prior to and upon Multisite Phosphorylation.
Sequence Determinants of the Conformational Properties of an Intrinsically Disordered Protein Prior to and upon Multisite Phosphorylation.
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DOI：
10.1021/jacs.6b10272
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发表时间：
2016-11-30
影响因子：
15
通讯作者：
Mittag T
中科院分区：
文献类型：
--
作者：
Martin EW;Holehouse AS;Grace CR;Hughes A;Pappu RV;Mittag T
许多细胞信号事件是由内在无序蛋白区域（IDRs）协调的，这些区域经历多位点丝氨酸/苏氨酸磷酸化。这些idr在多位点磷酸化之前和之后的构象性质与了解它们的功能直接相关。在这里，我们提出了生物物理研究和分子模拟的结果，量化了酿酒葡萄球菌转录因子Ash1的81个残基IDR的构象特性。我们发现，未磷酸化的Ash1 IDR采用卷状构象，扩展和良好的溶剂化。这一结果与基于脯氨酸含量低的idr的氨基酸组成的启发式推导出的关于全局压实的推论相矛盾。在十个不同位点磷酸化后，pAsh1的整体构象性质与未磷酸化的Ash1无法区分。这种不敏感源于局部和远程链内接触模式的代偿性变化。我们证明了Ash1和pAsh1的构象性质可以用脯氨酸和带电残基相对-à-vis所有其他残基的线性序列模式来解释。Ash1 IDR的序列特征与许多其他经历多位点磷酸化的IDR相同。因此，我们认为我们的发现可能可以推广到参与细胞信号传导的其他idr。
Many cell signaling events are coordinated by intrinsically disordered protein regions (IDRs) that undergo multisite Serine/Threonine phosphorylation. The conformational properties of these IDRs prior to and following multi-site phosphorylation are directly relevant to understanding their functions. Here, we present results from biophysical studies and molecular simulations that quantify the conformational properties of an 81-residue IDR from the S. cerevisiae transcription factor Ash1. We show that the unphosphorylated Ash1 IDR adopts coil-like conformations that are expanded and well-solvated. This result contradicts inferences regarding global compaction that are derived from heuristics based on amino acid compositions for IDRs with low proline contents. Upon phosphorylation at ten distinct sites, the global conformational properties of pAsh1 are indistinguishable from those of unphosphorylated Ash1. This insensitivity derives from compensatory changes to the pattern of local and long-range intra-chain contacts. We show that the conformational properties of Ash1 and pAsh1 can be explained in terms of the linear sequence patterning of proline and charged residues vis-à-vis all other residues. The sequence features of the Ash1 IDR are shared by many other IDRs that undergo multisite phosphorylation. Accordingly, we propose that our findings might be generalizable to other IDRs involved in cell signaling.
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影响因子：
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作者：
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通讯作者：
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