Dynamics of activation of lecithin:cholesterol acyltransferase by apolipoprotein A-I.
Dynamics of activation of lecithin:cholesterol acyltransferase by apolipoprotein A-I.
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DOI：
10.1021/bi901242k
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发表时间：
2009-12-01
期刊：
影响因子：
2.9
通讯作者：
Segrest, Jere P.
中科院分区：
文献类型：
--
作者：
Jones, Martin K.;Catte, Andrea;Li, Ling;Segrest, Jere P.
磷脂酰基链和未酯化的胆固醇（UC）通过卵磷脂：胆固醇酰基转移酶（LCAT）的酯交换反应的产物是胆固醇酯（CE）。载脂蛋白（apo）A-I激活新生（盘状）高密度脂蛋白（HDL）上的LCAT对于胆固醇逆向转运的抗动脉粥样硬化过程中成熟（球状）HDL的形成至关重要。在这里，我们报告的所有原子和粗粒（CG）分子动力学（MD）模拟HDL颗粒，有重大影响的机制LCAT激活。所有的原子和CG模拟提供支持的模型中，螺旋5/5结构域的apoA-I创建一个两亲性的“介绍隧道”，暴露在双层中心的酰基链的甲基末端溶剂。此外，CG模拟表明，UC也成为插入与其羟基部分（UC-OH）暴露于溶剂的两亲性呈现隧道的高效率;这些结果是一致的轨迹分析的全原子模拟显示，UC被集中在附近的呈现隧道。最后，与CE对富含CE的HDL的已知产物抑制一致，富含CE的球状HDL的CG模拟表明CE对两亲呈递通道的部分阻断。这些结果使我们提出以下工作假设：LCAT连接到盘状HDL后，apoA-I中的螺旋5/5结构域形成两亲呈递隧道，用于疏水酰基链和两亲UC从双层迁移到LCAT的磷脂酶A2样和酯化活性位点。这一假设目前正在测试的定点诱变。
The product of transesterification of phospholipid acyl chains and unesterified cholesterol (UC) by the enzyme lecithin: cholesterol acyltransferase (LCAT) is cholesteryl ester (CE). Activation of LCAT by apolipoprotein (apo) A-I on nascent (discoidal) high density lipoproteins (HDL) is essential for formation of mature (spheroidal) HDL during the antiatherogenic process of reverse cholesterol transport. Here we report all-atom and coarse grained (CG) molecular dynamics (MD) simulations of HDL particles that have major implications for mechanisms of LCAT activation. Both the all-atom and CG simulations provide support for a model in which the helix 5/5 domains of apoA-I create an amphipathic “presentation tunnel” that exposes methyl ends of acyl chains at the bilayer center to solvent. Further, CG simulations show that UC also becomes inserted with high efficiency into the amphipathic presentation tunnel with its hydroxyl moiety (UC-OH) exposed to solvent; these results are consistent with trajectory analyses of the all-atom simulations showing that UC is being concentrated in the vicinity of the presentation tunnel. Finally, consistent with known product inhibition of CE-rich HDL by CE, CG simulations of CE-rich spheroidal HDL indicate partial blockage of the amphipathic presentation tunnel by CE. These results lead us to propose the following working hypothesis: After attachment of LCAT to discoidal HDL, the helix 5/5 domains in apoA-I form amphipathic presentation tunnels for migration of hydrophobic acyl chains and amphipathic UC from the bilayer to the phospholipase A2-like and esterification active sites of LCAT, respectively. This hypothesis is currently being tested by site-directed mutagenesis.
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影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
DOI：
10.1073/pnas.94.23.12291
发表时间：
1997-11-11
影响因子：
11.1
作者：
Borhani, DW;Rogers, DP;Brouillette, CG
通讯作者：
Brouillette, CG
影响因子：
8
作者：
Bussell, R;Ramlall, TF;Eliezer, D
通讯作者：
Eliezer, D
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
4.8
作者：
Davidson, WS;Hilliard, GM
通讯作者：
Hilliard, GM