Structural basis for NHERF1 PDZ domain binding.
Structural basis for NHERF1 PDZ domain binding.
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DOI：
10.1021/bi201213w
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发表时间：
2012-04-10
期刊：
影响因子：
2.9
通讯作者：
Friedman, Peter A.
中科院分区：
文献类型：
--
作者：
Mamonova, Tatyana;Kurnikova, Maria;Friedman, Peter A.
Na+/H+交换调节因子-1（NHERF 1）是一种支架蛋白，其具有两个串联的PDZ结构域和羧基末端ezrin结合结构域（EBD）。甲状旁腺激素受体（PTHR）、II型钠依赖性磷酸盐协同转运蛋白（Npt 2a）和β2-肾上腺素能受体（β2-AR）通过其各自的羧基末端PDZ识别基序，分别与NHERF 1相互作用，形成具有其中一个PDZ结构域的复合物。在基础状态下，NHERF 1采用自抑制构象，其中其羧基末端PDZ配体与PDZ 2相互作用。我们应用分子动力学（MD）模拟，以揭示NHERF 1 PDZ结构域的结合选择性的结构和生化基础。PDZ 1独特地形成PDZ 2中不存在的几个接触，进一步稳定PDZ 1与靶配体的相互作用。计算PDZ 1和PDZ 2与形成PTHR、Npt 2a和β2-AR的PDZ识别基序的羧基末端5个氨基酸残基的结合自由能（ΔG），并与NHERF 1自缔合的计算ΔG进行比较。结果表明PTHR、β2-肾上腺素能和Npt 2a的相互作用涉及NHERF 1 PDZ结构域和靶蛋白之间的竞争。PDZ 2与PTHR的结合也可能与NHERF 1的自抑制构象竞争，从而有助于活性NHERF 1构象的稳定。
The Na+/H+ exchange regulatory factor-1 (NHERF1) is a scaffolding protein that possesses two tandem PDZ domains and a carboxy-terminal ezrin-binding domain (EBD). The parathyroid hormone receptor (PTHR), type II sodium-dependent phosphate co-transporter (Npt2a), and β2-adrenergic receptor (β2-AR), through their respective carboxy-terminal PDZ recognition motifs, individually interact with NHERF1 forming a complex with one of the PDZ domains. In the basal state, NHERF1 adopts a self-inhibited conformation, in which its carboxy-terminal PDZ ligand interacts with PDZ2. We applied Molecular Dynamics (MD) simulations to uncover the structural and biochemical basis for the binding selectivity of NHERF1 PDZ domains. PDZ1 uniquely forms several contacts not present in PDZ2 that further stabilize PDZ1 interactions with target ligands. The binding free energy (ΔG) of PDZ1 and PDZ2 with the carboxy-terminal, five-amino acid residues that form the PDZ-recognition motif of PTHR, Npt2a, and β2-AR was calculated and compared with the calculated ΔG for the self-association of NHERF1. The results suggest that the interaction of the PTHR, β2-adrenergic, and Npt2a involves competition between NHERF1 PDZ domains and the target proteins. The binding of PDZ2 with PTHR may also compete with the self-inhibited conformation of NHERF1, thereby contributing to the stabilization of an active NHERF1 conformation.
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