Structural basis for the association of PLEKHA7 with membrane-embedded phosphatidylinositol lipids.
Structural basis for the association of PLEKHA7 with membrane-embedded phosphatidylinositol lipids.
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DOI：
10.1016/j.str.2021.03.018
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发表时间：
2021-09-02
期刊：
影响因子：
--
通讯作者：
Marassi FM
中科院分区：
文献类型：
--
作者：
Aleshin AE;Yao Y;Iftikhar A;Bobkov AA;Yu J;Cadwell G;Klein MG;Dong C;Bankston LA;Liddington RC;Im W;Powis G;Marassi FM
PLEKHA7(PLEKHA7)在细胞内信号转导、细胞骨架组织和细胞黏附中起关键作用，与多种人类肿瘤的发生密切相关。PLEKHA7和其他PH结构域与膜磷脂酰肌醇磷脂(PIP)的相互作用是细胞定位和功能发挥的关键，但PLEKHA7和其他PH结构域与膜磷脂酰肌醇磷脂(PIP)的相互作用知之甚少。在这里，我们描述了PLEHA7识别膜结合的PIP的结构基础。通过X-射线结晶学、核磁共振、分子动力学模拟和等温滴定量热法，我们发现PLEKHA7与PIPs的相互作用是多价的，不同于离散的一对一相互作用，并且诱导了PIP的聚集。我们的发现揭示了膜组装在介导蛋白质-PIP结合中的中心作用，并为理解PH结构域如何参与PLEKHA7的信号传递、黏附和纳米聚集功能提供了路线图。PLEKHA7与膜结合磷脂酰肌醇(PIP)脂类的相互作用对细胞信号转导和细胞骨架组织至关重要。在这里，我们描述了它的PH域识别PIP的结构基础，并为理解这如何有助于PLEKHA7的功能提供了路线图。
PLEKHA7 (pleckstrin homology domain containing family A member 7) plays key roles in intracellular signaling, cytoskeletal organization and cell adhesion, and is associated with multiple human cancers. The interactions of its pleckstrin homology (PH) domain with membrane phosphatidyl-inositol-phosphate (PIP) lipids, are critical for proper cellular localization and function, but little is known about how PLEKHA7 and other PH domains interact with membrane-embedded PIPs. Here we describe the structural basis for recognition of membrane-bound PIPs by PLEHA7. Using X-ray crystallography, nuclear magnetic resonance (NMR), molecular dynamics (MD) simulations, and isothermal titration calorimetry (ITC), we show that the interaction of PLEKHA7 with PIPs is multivalent, distinct from a discrete one-to-one interaction, and induces PIP clustering. Our findings reveal a central role of the membrane assembly in mediating protein-PIP association and provide a roadmap for understanding how the PH domain contributes to the signaling, adhesion and nanoclustering functions of PLEKHA7. The interactions of PLEKHA7 with membrane-bound phosphatidylinositol (PIP) lipids are critical for cell signaling and cytoskeletal organization. Here we describe the structural basis for its PIP recognition by its PH domain and provide a roadmap for understanding how this contributes to the functions of PLEKHA7.
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DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
2.7
作者：
DELAGLIO, F;GRZESIEK, S;BAX, A
通讯作者：
BAX, A
影响因子：
4.8
作者：
Cao, Shufen;Chung, Stacey;Buck, Matthias
通讯作者：
Buck, Matthias
影响因子：
3.7
作者：
Awadalla MS;Thapa SS;Hewitt AW;Burdon KP;Craig JE
通讯作者：
Craig JE