Drug Discovery Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel.
Ella Lemelbaum Institute for Immuno-oncology, Sheba Medical Center, Ramat-Gan 526260, Israel.
Bioinformatics. 2020 Jun 1;36(12):3726-3732. doi: 10.1093/bioinformatics/btaa186.
Polyproline II (PPII) is a common conformation, comparable to α-helix and β-sheet. PPII, recently termed with a more generic name-κ-helix, adopts a left-handed structure with 3-fold rotational symmetry. Lately, a new type of binding mechanism-the helical lock and key model was introduced in SH3-domain complexes, where the interaction is characterized by a sliding helical pattern. However, whether this binding mechanism is unique only to SH3 domains is unreported.
Here, we show that the helical binding pattern is a universal feature of the κ-helix conformation, present within all the major target families-SH3, WW, profilin, MHC-II, EVH1 and GYF domains. Based on a geometric analysis of 255 experimentally solved structures, we found that they are characterized by a distinctive rotational angle along the helical axis. Furthermore, we found that the range of helical pitch varies between different protein domains or peptide orientations and that the interaction is also represented by a rotational displacement mimicking helical motion. The discovery of rotational interactions as a mechanism, reveals a new dimension in the realm of protein-protein interactions, which introduces a new layer of information encoded by the helical conformation. Due to the extensive involvement of the conformation in functional interactions, we anticipate our model to expand the current molecular understanding of the relationship between protein structure and function.
We have implemented the proposed methods in an R package freely available at https://github.com/Grantlab/bio3d.
Supplementary data are available at Bioinformatics online.
聚脯氨酸 II（PPII）是一种常见的构象，类似于α-螺旋和β-折叠。PPII，最近被赋予了一个更通用的名称-κ-螺旋，采用左手结构，具有 3 重旋转对称性。最近，一种新的结合机制——螺旋锁钥模型被引入 SH3 结构域复合物中，其中的相互作用以滑动螺旋模式为特征。然而，这种结合机制是否仅存在于 SH3 结构域中还没有报道。
在这里，我们表明，螺旋结合模式是κ-螺旋构象的普遍特征，存在于所有主要的靶家族-SH3、WW、原肌球蛋白、MHC-II、EVH1 和 GYF 结构域中。基于对 255 个实验确定结构的几何分析，我们发现它们的特征是沿螺旋轴的独特旋转角度。此外，我们发现螺旋螺距的范围在不同的蛋白质结构域或肽取向之间变化，并且相互作用也通过模拟螺旋运动的旋转位移来表示。作为一种机制的旋转相互作用的发现，揭示了蛋白质-蛋白质相互作用领域的一个新维度，它引入了一个由螺旋构象编码的新的信息层。由于构象在功能相互作用中的广泛参与，我们预计我们的模型将扩展当前对蛋白质结构和功能之间关系的分子理解。
我们已经在一个免费的 R 包中实现了所提出的方法，可在 https://github.com/Grantlab/bio3d 上获得。
补充数据可在 Bioinformatics 在线获得。
