Department of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.
Arch Biochem Biophys. 2013 Dec;540(1-2):9-18. doi: 10.1016/j.abb.2013.10.001. Epub 2013 Oct 7.
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor that mediates the recognition, the binding and internalization of ox-LDL. A truncated soluble form of LOX-1 (sLOX-1) has been identified that, at elevated levels, has been associated to acute coronary syndrome. Human sLOX-1 is the extracellular part of membrane LOX-1 which is cleaved in the NECK domain with a mechanism that has not yet been identified. Purification of human sLOX-1 has been carried out to experimentally identify the cleavage site region within the NECK domain. Molecular modelling and classical molecular dynamics simulation techniques have been used to characterize the structural and dynamical properties of the LOX-1 NECK domain in the presence and absence of the CTLD recognition region, taking into account the obtained proteolysis results. The simulative data indicate that the NECK domain is stabilized by the coiled-coil heptad repeat motif along the simulations, shows a definite flexibility pattern and is characterized by specific electrostatic potentials. The detection of a mobile inter-helix space suggests an explanation for the in vivo susceptibility of the NECK domain to the proteolytic cleavage, validating the assumption that the NECK domain sequence is composed of a coiled-coil motif destabilized in specific regions of functional significance.
凝集素样氧化型低密度脂蛋白受体-1（LOX-1）是一种清道夫受体，介导对氧化型 LDL 的识别、结合和内化。已经鉴定出 LOX-1 的一种截断可溶性形式（sLOX-1），其在升高的水平与急性冠状动脉综合征相关。人 sLOX-1 是人膜 LOX-1 的细胞外部分，其在 NECK 结构域中通过尚未确定的机制被切割。已经进行了人 sLOX-1 的纯化，以实验鉴定 NECK 结构域中的切割位点区域。已经使用分子建模和经典分子动力学模拟技术来表征 LOX-1 NECK 结构域在存在和不存在 CTLD 识别区域时的结构和动力学特性，同时考虑到获得的蛋白水解结果。模拟数据表明，NECK 结构域在整个模拟过程中沿着卷曲螺旋七肽重复基序稳定，表现出明确的柔韧性模式，并具有特定的静电势。检测到一个可移动的螺旋间空间，这为 NECK 结构域在体内易受蛋白水解切割的原因提供了一个解释，验证了这样的假设，即 NECK 结构域序列由在功能重要的特定区域不稳定的卷曲螺旋基序组成。
