具有SH3的聚脯氨酸II构象的螺旋锁和钥匙模型。,Bioinformatics

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具有SH3的聚脯氨酸II构象的螺旋锁和钥匙模型。
Bioinformatics ( IF 4.4 ) Pub Date : 2020-01-01 , DOI: 10.1093/bioinformatics/btz527
Tomer Meirson _{1,

2} , David Bomze ₃ , Liron Kahlon ₄ , Hava Gil-Henn ₂ , Abraham O Samson ₁

Affiliation

动机超过一半的人类蛋白质组包含富含脯氨酸的基序PxxP。该基序极有可能采用左旋聚脯氨酸II（PPII）螺旋，并可能结合SH3域。根据PPII是按正向（N对C末端）还是负向（C对N末端）结合，SH3域通常分为两类。自从六十多年前发现该结构基序以来，对其结合的系统理解仍然很薄，与SH3结构域结合的共有氨基酸序列仍然不清楚。结果在这里，我们表明PPII与SH3结构域的相互作用受螺旋骨架及其脯氨酸的控制，以及它们绕PPII螺旋轴的旋转角度。根据对131个与PPII复配的，实验性解析的SH3域的几何分析，我们观察到了沿螺旋螺杆轴线的旋转平移，并将它们按120°分为三类，分别命名为α（0-120°），β（120-240°）和γ（240-360°）。此外，我们发现PPII螺旋的特征是PxxP基序的移动，其前是带正电荷的残基，这些残基起着结构阅读框的作用，并决定了SH3结构域的组织。但是，对于所有分类的PPII，没有一个单一的共有基序。我们的结果证明了一种具有旋转和平移钥匙的锁具的卓越装置，而该装置在分子生物学中尚无已知等效装置。我们预计我们的模型将成为解密PPII代码的起点，而PPII代码可以使我们对蛋白质结构与功能之间的关系的理解呈指数增长。可用性和实现我们已经在R软件环境中以及在https://github.com/Grantlab/bio3d免费提供的R包中实现了所建议的方法。补充信息补充数据可从Bioinformatics在线获得。

"点击查看英文标题和摘要"

A helical lock and key model of polyproline II conformation with SH3.

MOTIVATION More than half of the human proteome contains the proline-rich motif, PxxP. This motif has a high propensity for adopting a left-handed polyproline II (PPII) helix and can potentially bind SH3 domains. SH3 domains are generally grouped into two classes, based on whether the PPII binds in a positive (N-to-C terminal) or negative (C-to-N terminal) orientation. Since the discovery of this structural motif, over six decades ago, a systematic understanding of its binding remains poor and the consensus amino acid sequence that binds SH3 domains is still ill defined. RESULTS Here, we show that the PPII interaction with SH3 domains is governed by the helix backbone and its prolines, and their rotation angle around the PPII helical axis. Based on a geometric analysis of 131 experimentally solved SH3 domains in complex with PPIIs, we observed a rotary translation along the helical screw axis, and separated them by 120° into three categories we name α (0-120°), β (120-240°) and γ (240-360°). Furthermore, we found that PPII helices are distinguished by a shifting PxxP motif preceded by positively charged residues which act as a structural reading frame and dictates the organization of SH3 domains; however, there is no one single consensus motif for all classified PPIIs. Our results demonstrate a remarkable apparatus of a lock with a rotating and translating key with no known equivalent machinery in molecular biology. We anticipate our model to be a starting point for deciphering the PPII code, which can unlock an exponential growth in our understanding of the relationship between protein structure and function. AVAILABILITY AND IMPLEMENTATION We have implemented the proposed methods in the R software environment and in an R package freely available at https://github.com/Grantlab/bio3d. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

更新日期：2019-06-29

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