Physicochemical principles that regulate the competition between functional and dysfunctional association of proteins
Physicochemical principles that regulate the competition between functional and dysfunctional association of proteins
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DOI：
10.1073/pnas.0812414106
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发表时间：
2009-06-23
影响因子：
11.1
通讯作者：
Vendruscolo, Michele
中科院分区：
文献类型：
--
作者：
Pechmann, Sebastian;Levy, Emmanuel D.;Vendruscolo, Michele
为了维持蛋白质的动态平衡，各种质量控制机制，如未折叠的蛋白质反应和热休克反应，使蛋白质能够折叠并组装成功能复合体，同时避免形成异常的和潜在的有害聚集体。我们在这里表明，蛋白质之间相互作用的调节是由它们的氨基酸序列的物理化学性质提供的。对蛋白质数据库(PDB)中蛋白质-蛋白质复合体的系统分析结果表明，界面区域比其他表面区域更容易聚集，这表明许多促进功能复合体形成的相互作用，包括疏水和静电力，也可能导致异常的分子间结合。然而，我们也表明，通过二硫键和盐桥将聚集倾向的界面稳定在其功能构象中，从而防止了易于聚集的界面触发不受控制的组装。这些结果表明，蛋白质的功能和功能失调的结合是由类似的力促进的，但它们也受到稳定自然状态的特定相互作用的密切调控。
To maintain protein homeostasis, a variety of quality control mechanisms, such as the unfolded protein response and the heat shock response, enable proteins to fold and to assemble into functional complexes while avoiding the formation of aberrant and potentially harmful aggregates. We show here that a complementary contribution to the regulation of the interactions between proteins is provided by the physicochemical properties of their amino acid sequences. The results of a systematic analysis of the protein-protein complexes in the Protein Data Bank (PDB) show that interface regions are more prone to aggregate than other surface regions, indicating that many of the interactions that promote the formation of functional complexes, including hydrophobic and electrostatic forces, can potentially also cause abnormal intermolecular association. We also show, however, that aggregation-prone interfaces are prevented from triggering uncontrolled assembly by being stabilized into their functional conformations by disulfide bonds and salt bridges. These results indicate that functional and dysfunctional association of proteins are promoted by similar forces but also that they are closely regulated by the presence of specific interactions that stabilize native states.