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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Identification of the PDZ3 Domain of the Adaptor Protein PDZK1 as a Second Physiologically Functional Binding Site for the C Terminus of the High Density Lipoprotein Receptor Scavenger Receptor Class B Type I
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Identification of the PDZ3 Domain of the Adaptor Protein PDZK1 as a Second Physiologically Functional Binding Site for the C Terminus of the High Density Lipoprotein Receptor Scavenger Receptor Class B Type I

机译：适配器蛋白PDZK1的PDZ3结构域的鉴定为高密度脂蛋白受体清除剂受体I类B的C末端的第二个生理功能结合位点

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摘要

The normal expression, cell surface localization, and function of the murine high density lipoprotein receptor scavenger receptor class B type I (SR-BI) in hepatocytes in vivo, and thus normal lipoprotein metabolism, depend on its four PDZ domain (PDZ1–PDZ4) containing cytoplasmic adaptor protein PDZK1. Previous studies showed that the C terminus of SR-BI (“target peptide”) binds directly to PDZ1 and influences hepatic SR-BI protein expression. Unexpectedly an inactivating mutation in PDZ1 (Tyr20 → Ala) only partially, rather than completely, suppresses the ability of PDZK1 to control hepatic SR-BI. We used isothermal titration calorimetry to show that PDZ3, but not PDZ2 or PDZ4, can also bind the target peptide (Kd = 37.0 μm), albeit with ∼10-fold lower affinity than PDZ1. This binding is abrogated by a Tyr253 → Ala substitution. Comparison of the 1.5-Å resolution crystal structure of PDZ3 with its bound target peptide (505QEAKL509) to that of peptide-bound PDZ1 indicated fewer target peptide stabilizing atomic interactions (hydrogen bonds and hydrophobic interactions) in PDZ3. A double (Tyr20 → Ala (PDZ1) + Tyr253 → Ala (PDZ3)) substitution abrogated all target peptide binding to PDZK1. In vivo hepatic expression of a singly substituted (Tyr253 → Ala (PDZ3)) PDZK1 transgene (Tg) was able to correct all of the SR-BI-related defects in PDZK1 knock-out mice, whereas the doubly substituted [Tyr20 → Ala (PDZ1) + Tyr253 → Ala (PDZ3)]Tg was unable to correct these defects. Thus, we conclude that PDZK1-mediated control of hepatic SR-BI requires direct binding of the SR-BI C terminus to either the PDZ1 or PDZ3 domains, and that binding to both domains simultaneously is not required for PDZK1 control of hepatic SR-BI.
机译：小鼠肝细胞中B型I型鼠高密度脂蛋白受体清道夫受体的正常表达，细胞表面定位和功能，以及因此脂蛋白的正常代谢，取决于其四个PDZ结构域（PDZ1-PDZ4）含有胞质衔接蛋白PDZK1。先前的研究表明，SR-BI（“目标肽”）的C末端直接与PDZ1结合并影响肝SR-BI蛋白的表达。出乎意料的是，PDZ1（Tyr 20 →Ala）的失活突变仅部分而非完全抑制了PDZK1控制肝脏SR-BI的能力。我们使用等温滴定量热法显示，PDZ3而非PDZ2或PDZ4也可以结合靶肽（Kd = 37.0μm），尽管亲和力比PDZ1低约10倍。 Tyr 253 →Ala取代消除了这种结合。 PDZ3及其结合的靶肽（ 505 QEAKL 509 ）与结合肽的PDZ1的1.5-Å分辨率晶体结构的比较表明，稳定肽原子相互作用的靶肽较少（氢键和疏水性相互作用）。双（Tyr 20 →Ala（PDZ1）+ Tyr 253 →Ala（PDZ3））取代消除了所有与PDZK1结合的靶肽。单取代的（Tyr 253 →Ala（PDZ3））PDZK1转基因（Tg）的体内肝表达能够纠正PDZK1敲除小鼠中所有与SR-BI相关的缺陷，而双取代[Tyr 20 →Ala（PDZ1）+ Tyr 253 →Ala（PDZ3）] Tg无法纠正这些缺陷。因此，我们得出结论，PDZK1介导的对肝SR-BI的控制需要SR-BI C末端与PDZ1或PDZ3域的直接结合，并且PDZK1对肝SR-BI的控制不需要同时与两个域结合。

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