Structural determinants of the Na+/H+ exchanger regulatory factor interaction with the β2 adrenergic and platelet-derived growth factor receptors
Structural determinants of the Na+/H+ exchanger regulatory factor interaction with the β2 adrenergic and platelet-derived growth factor receptors
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DOI：
10.1074/jbc.m201507200
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发表时间：
2002-05-24
影响因子：
4.8
通讯作者：
Ladias, JAA
中科院分区：
文献类型：
--
作者：
Karthikeyan, S;Leung, TL;Ladias, JAA
Na+/H+交换调节因子（NHERF）通过其PDZ 1结构域分别与β 2肾上腺素能受体（β 2 AR）和血小板衍生生长因子受体的羧基末端序列NDSLL和EDSFL结合，并在这些受体的膜定位和生理调节中发挥关键作用。结合到序列NDSLL和EDSFL的人NHERF PDZ 1结构域的晶体结构已分别在1.9和2.2埃分辨率下确定。β（2）AR和血小板衍生生长因子受体配体通过β折叠增强过程插入PDZ 1结合口袋，并通过氢键和疏水接触的基本相似的网络稳定。在PDZ 1-β（2）AR复合物中，β（2）AR肽-4位的天冬酰胺侧链与PDZ 1的Gly（30）形成两个额外的氢键，这有助于这种相互作用的更高亲和力。值得注意的是，两种复合物通过涉及肽配体的倒数第二个氨基酸的侧链的疏水相互作用进一步稳定，而PDZ 1残基Asn（22）和Glu（43）经历构象变化以适应这些侧链。这些结果提供了对肽配体位置-1处的不同侧链与PDZ结构域相互作用的机制的结构见解，并有助于PDZ-配体相互作用的亲和力。
The Na+/H+ exchanger regulatory factor (NHERF) binds through its PDZ1 domain to the carboxyl-terminal sequences NDSLL and EDSFL of the beta(2) adrenergic receptor (beta(2)AR) and platelet-derived growth factor receptor, respectively, and plays a critical role in the membrane localization and physiological regulation of these receptors. The crystal structures of the human NHERF PDZ1 domain bound to the sequences NDSLL and EDSFL have been determined at 1.9- and 2.2-Angstrom resolution, respectively. The beta(2)AR and platelet-derived growth factor receptor ligands insert into the PDZ1 binding pocket by a beta-sheet augmentation process and are stabilized by largely similar networks of hydrogen bonds and hydrophobic contacts. In the PDZ1-beta(2)AR complex, the side chain of asparagine at position -4 in the beta(2)AR peptide forms two additional hydrogen bonds with Gly(30) of PDZ1, which contribute to the higher affinity of this interaction. Remarkably, both complexes are further stabilized by hydrophobic interactions involving the side chains of the penultimate amino acids of the peptide ligands, whereas the PDZ1 residues Asn(22) and Glu(43) undergo conformational changes to accommodate these side chains. These results provide structural insights into the mechanisms by which different side chains at the position -1 of peptide ligands interact with PDZ domains and contribute to the affinity of the PDZ-ligand interaction.