Department of Biology, Hong Kong University of Science and Technology, Hong Kong, China.
Adv Exp Med Biol. 2012;725:106-25. doi: 10.1007/978-1-4614-0659-4_7.
Interactions between Intrinsically Disordered Protein Regions (IDRs) and their targets commonly exhibit localised contacts via target-induced disorder to order transitions. Other more complex IDR target interactions have been termed "fuzzy" because the IDR does not form a well-defined induced structure. In some remarkable cases of fuzziness IDR function is apparently sequence independent and conferred by amino acid composition. Such cases have been referred to as "random fuzziness" but the molecular features involved are poorly characterised. The transcriptional activation domain (EAD) of oncogenic Ewing's Sarcoma Fusion Proteins (EFPs) is an ≈280 residue IDR with a biased composition restricted to Ala, Gly, Gln, Pro, Ser, Thr and Tyr. Multiple aromatic side chains (exclusively from Try residues) and the particular EAD composition are crucial for molecular recognition but there appears to be no other major geometrically constrained requirement. Computational analysis of the EAD using PONDR (Molecular Kinetics, Inc. http://www.pondr. com) complements the functional data and shows, accordingly, that propensity for structural order within the EAD is conferred by Tyr residues. To conclude, molecular recognition by the EAD is extraordinarily malleable and involves multiple aromatic contacts facilitated by a flexible peptide backbone and, most likely, a limited number of weaker contributions from amenable side chains. I propose to refer to this mode of fuzzy recognition as "polyaromatic", noting that it shares some fundamental features with the "polyelectrostatic" (phosphorylation-dependent) interaction of the Sic1 Cdk inhibitor and Cdc4._I will also speculate on more detailed models for molecular recognition by the EAD and their relationship to native (non-oncogenic) EAD function.
蛋白质无规则区域（IDR）与其靶标之间的相互作用通常通过靶标诱导的无序到有序转变来表现为局部接触。其他更复杂的 IDR 靶标相互作用被称为“模糊”，因为 IDR 不会形成明确的诱导结构。在一些模糊 IDR 功能明显与序列无关且由氨基酸组成决定的显著情况下。这种情况被称为“随机模糊性”，但涉及的分子特征描述得很差。致癌性尤文肉瘤融合蛋白（EFPs）的转录激活结构域（EAD）是一个约 280 个残基的 IDR，其组成偏向于 Ala、Gly、Gln、Pro、Ser、Thr 和 Tyr。多个芳香侧链（仅来自 Try 残基）和特定的 EAD 组成对于分子识别至关重要，但似乎没有其他主要的几何约束要求。使用 PONDR（Molecular Kinetics，Inc. http://www.pondr.com）对 EAD 进行计算分析补充了功能数据，并相应地表明，EAD 内结构有序的倾向是由 Tyr 残基赋予的。总之，EAD 的分子识别具有非凡的可塑性，涉及多个芳香接触，由灵活的肽骨架和（很可能）来自适宜侧链的有限数量的较弱贡献来促进。我建议将这种模糊识别模式称为“多芳香”，并注意到它与 Sic1 Cdk 抑制剂和 Cdc4 的“多静电”（磷酸化依赖性）相互作用具有一些基本特征。我还将推测 EAD 分子识别的更详细模型及其与天然（非致癌）EAD 功能的关系。
