Specificity of ligand-induced conformational change of lipoprotein(a).
Specificity of ligand-induced conformational change of lipoprotein(a).
复制标题
配体诱导的脂蛋白构象变化的特异性(a)。
DOI：
10.1021/bi9706982
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发表时间：
1997
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;Santiago,JY;FurbeeJr,J;Meredith,SC
用一系列ω-氨基羧酸和6-氨基己酸（6-AHA）的类似物对Lp（a）的构象进行了研究。使用粘度校正的沉降系数，六个额外的配体被证明诱导Lp（a）的主要构象变化，从紧凑的形式到扩展的形式。它们是反式-4-（氨甲基）环己烷羧酸（t-AMCHA）、脯氨酸、4-氨基丁酸、8-氨基辛酸、Nα-乙酰赖氨酸和甘氨酸。确定赖氨酸、Nε-乙酰赖氨酸、谷氨酸和己二酸不会引起构象变化。在上述配体展开Lp（a）的浓度下，尿素和盐酸胍在诱导这种构象变化方面是无效的。构象变化被抑制100 mM NaCl和在较小程度上由20 mM谷氨酸钠。尽管事实上，这两种盐具有几乎相同的离子强度，更大的抑制NaCl的展开是一致的，提出了稳定的kringle相互作用的氯离子。在最接近生理条件的100 mM NaCl中，只有脯氨酸、4-氨基丁酸、6-AHA和t-AMCHA是有效的配体。通过分析构象改变配体的尺寸，我们提出，在确定配体在破坏Lp（a）的有效性的关键变量是配体的羧基和胺官能团之间的距离。最佳距离约为6 μ m，这与观察到的已知纤溶酶原和载脂蛋白（a）赖氨酸结合位点的阳离子和阴离子中心分离6.6−6.8 μ m一致。这些研究对Lp（a）粒子的组装机制有一定的意义。
The conformation of Lp(a) was probed with a set of ω-aminocarboxylic acids and other analogs of 6-aminohexanoic acid (6-AHA). Using the viscosity-corrected sedimentation coefficient, six additional ligands were shown to induce a major conformational change in Lp(a), from a compact form to an extended form. These weretrans-4-(aminomethyl)cyclohexanecarboxylic acid (t-AMCHA), proline, 4-aminobutyric acid, 8-aminooctanoic acid,Nα-acetyllysine, and glycine. Lysine,Nε-acetyllysine, glutamic acid, and adipic acid were determined not to cause a conformational change. Urea and guanidine hydrochloride were ineffective at inducing this conformational change at concentrations at which the above ligands did unfold Lp(a). The conformational change was inhibited by 100 mM NaCl and to a lesser extent by 20 mM sodium glutamate. Despite the fact that these two salts have nearly the same ionic strengths, the greater inhibition of the unfolding by NaCl is consistent with a proposed stabilization of interkringle interactions by chloride ions. In 100 mM NaCl, which most closely resembles physiological conditions, only proline, 4-aminobutyric acid, 6-AHA, and t-AMCHA were effective ligands. By analyzing the dimensions of the conformation altering ligands, we propose that a critical variable in determining the effectiveness of a ligand in disrupting Lp(a) is the distance between the carboxyl and amine functions of the ligand. The optimal distance is approximately 6 Å, which agrees with the observed 6.6−6.8 Å separation of the cationic and anionic centers of known plasminogen and apo(a) lysine binding sites. These studies have implications for the mechanism of Lp(a) particle assembly.