Ligand-induced conformational change of lipoprotein(a).
Ligand-induced conformational change of lipoprotein(a).
复制标题
配体诱导的脂蛋白构象变化(a)。
DOI：
10.1021/bi951792q
复制
发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Meredith,SC
中科院分区：
文献类型：
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作者：
Fless,GM;FurbeeJr,J;Snyder,ML;Meredith,SC
脂蛋白(a)在结合6-氨基己酸（6-AHA）时经历了一个戏剧性的、可逆的构象变化，通过沉降率的降低来测量，其幅度与载脂蛋白(a)质量成正比。纤溶酶原在占据弱赖氨酸结合位点时也发生类似的从紧凑型到扩展型的可逆转变。大载脂蛋白(a)的Lp(a)的变化幅度约为纤溶酶原的2.5倍。无论载脂蛋白(a)大小如何，结合分析表明，每Lp(a)颗粒结合1.4−4个6-AHA分子；构象变化的中点发生在6-AHA浓度为100 ~ 200 mM时。由于恒河Lp(a)缺乏kringle V和kringle IV 10上的强赖氨酸结合位点，也经历了类似的构象变化，这一现象可能归因于弱位点，可能位于K-IV 5 ~ 8。致密Lp(a)，即天然Lp(a)，其摩擦比（f/fo）为1.2，与载脂蛋白(a)质量无关，表明其形状和水合作用不变。对于饱和6-AHA的Lp(a)，当K-IV为32时，最大载脂蛋白(a)的f/从1.5变为超过2.1，表明水动力体积与kringles数之间存在线性关系，这与扩展构象的预期一致。然而，只有以K-IV 2结构域为代表的载脂蛋白(a)的可变部分参与构象变化；不变的K-IV 3−9结构域仍然靠近表面。这些结果表明，apo(a)通过弱赖氨酸结合位点与apoB和/或apo(a)上的多个赖氨酸之间的相互作用维持在紧密状态，而这些相互作用可以被6-AHA（赖氨酸类似物）破坏。
Lipoprotein(a) undergoes a dramatic, reversible conformational change on binding 6-aminohexanoic acid (6-AHA), as measured by a decrease in the sedimentation rate, the magnitude of which is directly proportional to apo(a) mass. A similar reversible transition from a compact to an extended form has been shown to occur in plasminogen on occupation of a weak lysine binding site. The magnitude of the change in Lp(a) with large apo(a) is about 2.5 times that seen for plasminogen, however. Regardless of apo(a) size, binding analysis indicated that 1.4−4 molecules of 6-AHA bound per Lp(a) particle; the midpoint of the conformational change occurs at 6-AHA concentrations of 100−200 mM. Since rhesus Lp(a), which lacks both kringle V and the strong lysine binding site on kringle IV 10, also undergoes a similar conformational change, the phenomenon may be attributable to weak sites, possibly located in K-IV 5−8. Compact Lp(a), i.e., native Lp(a), had a frictional ratio (f/fo) of 1.2 that was independent of apo(a) mass, implying constant shape and hydration. For Lp(a) in saturating 6-AHA,f/foranged from 1.5 to over 2.1 for the largest apo(a) with 32 K-IV, indicating a linear relationship between hydrodynamic volume and number of kringles, as expected for an extended conformation. However, only the variable portion of apo(a) represented by the K-IV 2 domains, participates in the conformational change; the invariant K-IV 3−9 domains remain close to the surface. These results suggest that apo(a) is maintained in a compact state through interactions between weak lysine binding sites and multiple lysines on apoB and/or apo(a), and that these interactions can be disrupted by 6-AHA, a lysine analog.