文章基本信息

标题：Identification of amino acid residues in the ligand binding repeats of LDL receptor important for PCSK9 binding
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作者：Shi-jun Deng ; Shi-jun Deng ; Adekunle Alabi 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2019
卷号：60
期号：3
页码：516-527
DOI：10.1194/jlr.M089193
出版社：American Society for Biochemistry and Molecular Biology
摘要：Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes LDL receptor (LDLR) degradation, increasing plasma levels of LDL cholesterol and the risk of cardiovascular disease. We have previously shown that, in addition to the epidermal growth factor precursor homology repeat-A of LDLR, at least three ligand-binding repeats (LRs) of LDLR are required for PCSK9-promoted LDLR degradation. However, how exactly the LRs contribute to PCSK9’s action on the receptor is not completely understood. Here, we found that substitution of Asp at position 172 in the linker between the LR4 and LR5 of full-length LDLR with Asn (D172N) reduced PCSK9 binding at pH 7.4 (mimic cell surface), but not at pH 6.0 (mimic endosomal environment). On the other hand, mutation of Asp at position 203 in the LR5 of full-length LDLR to Asn (D203N) significantly reduced PCSK9 binding at both pH 7.4 and pH 6.0. D203N also significantly reduced the ability of LDLR to mediate cellular LDL uptake, whereas D172N had no detectable effect. These findings indicate that amino acid residues in the LRs of LDLR play an important role in PCSK9 binding to the receptor.
关键词：LDL binding ; hypercholesterolemia ; atherosclerosis ; site-directed mutagenesis