Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Nat Commun. 2013;4:2037. doi: 10.1038/ncomms3037.
Protein functions are largely affected by their conformations. This is exemplified in proteins containing modular domains. However, the evolutionary dynamics that define and adapt the conformation of such modular proteins remain elusive. Here we show that cis-interactions between the C-terminal phosphotyrosines and SH2 domain within the protein tyrosine phosphatase Shp2 can be tuned by an adaptor protein, Grb2. The competitiveness of two phosphotyrosines, namely pY542 and pY580, for cis-interaction with the same SH2 domain is governed by an antagonistic combination of contextual amino acid sequence and position of the phosphotyrosines. Specifically, pY580 with the combination of a favourable position and an adverse sequence has an overall advantage over pY542. Swapping the sequences of pY542 and pY580 results in one dominant form of cis-interaction and subsequently inhibits the trans-regulation by Grb2. Thus, the antagonistic combination of sequence and position may serve as a basic design principle for proteins with tunable conformations.
蛋白质的功能在很大程度上受到其构象的影响。这在含有模块域的蛋白质中得到了例证。然而，定义和适应这种模块化蛋白质构象的进化动态仍然难以捉摸。在这里，我们表明，蛋白酪氨酸磷酸酶 Shp2 中的 C 端磷酸酪氨酸和 SH2 结构域之间的顺式相互作用可以被衔接蛋白 Grb2 调节。两个磷酸酪氨酸（即 pY542 和 pY580）与相同的 SH2 结构域顺式相互作用的竞争能力由上下文氨基酸序列和磷酸酪氨酸位置的拮抗组合来控制。具体来说，具有有利位置和不利序列的 pY580 总体上优于 pY542。交换 pY542 和 pY580 的序列会导致一种主要的顺式相互作用形式，并随后抑制 Grb2 的转调控。因此，序列和位置的拮抗组合可能是具有可调节构象的蛋白质的基本设计原则。
