Structural implication for the impaired binding of W150A mutant LOX-1 to oxidized low density lipoprotein, OxLDL
- 作者：Shogo Nakano ; Mamoru Sugihara ; Risato Yamada ; Katsuo Katayanagi ; Shin-ichi Tate ; tate@hiroshima-u.ac.jp
- 关键词：C-type lectin-like domain ; Oxidized low density lipoprotein ; Atherosclerosis ; Receptor structure ; Pattern recognition receptor
- 刊名：Biochimica et Biophysica Acta - Proteins and Proteomics
- 出版年：2012
- 期刊代码：161_15709639
- 类别：bio
- 出版时间：May, 2012
- 卷：1824
- 期：5
- 页码：739-749
- 文件大小：2265 K
摘要
Lectin-like oxidized lipoprotein (OxLDL) receptor 1, LOX-1, is the major OxLDL receptor expressed on vascular endothelial cells. We have previously reported the ligand-recognition mode of LOX-1 based on the crystal structure of the ligand binding domain (C-type lectin-like domain, CTLD) and surface plasmon resonance analysis, which suggested that the functional significance of the CTLD dimer (the 鈥榗anonical鈥?dimer) is to harbor the characteristic 鈥渂asic spine鈥?on its surface. In this study, we have identified the key inter-domain interactions in retaining the canonical CTLD dimer by X-ray structural analysis of the inactive mutant W150A CTLD. The canonical CTLD dimer forms through tight hydrophobic interactions, in which W150 engages in a lock-and-key manner and represents the main interaction. The loss of the Trp ring by mutation to Ala prevents the formation of the canonical dimer, as elucidated from docking calculations using the crystal structure of W150A CTLD. The results emphasize that the canonically formed CTLD dimer is essential for LOX-1 to bind to OxLDL, which supports our proposed view that the basic spine surface present in the correctly formed dimer plays a primal role in OxLDL recognition. This concept provides insight into the pathogenic pattern recognized by LOX-1 as a member of the pattern recognition receptors.