Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0378, USA.
J Mol Biol. 2010 Apr 30;398(2):306-19. doi: 10.1016/j.jmb.2010.03.022. Epub 2010 Mar 19.
Clusters of complement-type ligand-binding repeats (CRs) in the low-density lipoprotein receptor (LDLR) family are thought to mediate the interactions with their various ligands. Apolipoprotein E (ApoE), a key ligand for cholesterol homeostasis, has been shown to interact with LDLR-related protein 1 (LRP) through these clusters. The segment comprising the receptor-binding portion of ApoE (residues 130-149) has been found to have a weak affinity for isolated CRs. We have fused this region of ApoE to a high-affinity CR from LRP (CR17) for structural elucidation of the complex. The interface reveals a motif that has previously been observed in CR domains with other binding partners, but with several novel features. Comparison to free CR17 reveals that very few structural changes result from this binding event, but significant changes in intrinsic dynamics are observed upon binding. NMR perturbation experiments suggest that this interface may be similar to several other ligand interactions with LDLRs.
低密度脂蛋白受体(LDLR)家族中的补体型配体结合重复簇(CRs)被认为介导与各种配体的相互作用。载脂蛋白 E(ApoE)是胆固醇稳态的关键配体,已被证明通过这些簇与 LDLR 相关蛋白 1(LRP)相互作用。已发现载脂蛋白 E(残基 130-149)的受体结合部分的片段对分离的 CRs 具有较弱的亲和力。我们已将 ApoE 的该区域融合到 LRP 的高亲和力 CR 上,用于复合物的结构阐明。该界面揭示了一个先前在与其他结合伙伴的 CR 结构域中观察到的模体,但具有一些新的特征。与游离的 CR17 进行比较表明,这种结合事件几乎不会导致结构发生变化,但在结合时会观察到固有动力学的显著变化。NMR 扰动实验表明,该界面可能与 LDLR 与其他几种配体的相互作用相似。