Solution structure of the LDL receptor EGF-AB pair: a paradigm for the assembly of tandem calcium binding EGF domains.
Solution structure of the LDL receptor EGF-AB pair: a paradigm for the assembly of tandem calcium binding EGF domains.
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LDL 受体 EGF-AB 对的溶液结构：串联钙结合 EGF 结构域组装的范例。
DOI：
10.1016/s0969-2126(01)00606-2
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发表时间：
2001
期刊：
影响因子：
5.7
通讯作者：
A. Downing
中科院分区：
文献类型：
--
作者：
S. Saha;Jonathan Boyd;J. Werner;V. Knott;P. Handford;Iain D. Campbell;A. Downing
背景：通过对人表皮生长因子样蛋白（EGF）的一对钙结合（cb）结构域的结构和序列的观察，我们认为cbEGF结构域的串联结构具有保守的相对构象。低密度脂蛋白受体（LDLR），这是功能无关的表皮生长因子-1，包含一个单一的一对域，被选为研究在验证这一假设。LDLR是蛋白质，是有缺陷的家族性高胆固醇血症，一种常见的遗传性疾病，易使个人心血管并发症和过早death.Results：在这里，我们提出的解决方案结构的前两个EGF域的LDL受体，确定使用传统的NMR限制和残留的偶极耦合。cbEGF结构域具有延长的棒状排列，如预测的那样。新的结构允许详细评估与家族性高胆固醇血症相关的突变的后果maintained.Conclusions：EGF结构域的功能不同的蛋白质中的保守安排的验证结构基因组学具有重要意义，因为多个串联cbEGF对已被确定在许多必需的蛋白质，有牵连的人类疾病。我们的研究结果提供了使用同源建模来探测这个不同蛋白质家族中的结构-功能关系的方法，并可能在未来设计新的诊断和治疗方法。
Background:From the observed structure and sequence of a pair of calcium binding (cb) epidermal growth factor-like (EGF) domains from human fibrillin-1, we proposed that many tandem cbEGF domains adopt a conserved relative conformation. The low-density lipoprotein receptor (LDLR), which is functionally unrelated to fibrillin-1, contains a single pair of EGF domains that was chosen for study in the validation of this hypothesis. The LDLR is the protein that is defective in familial hypercholesterolaemia, a common genetic disorder that predisposes individuals to cardiovascular complications and premature death.Results:Here, we present the solution structure of the first two EGF domains from the LDL receptor, determined using conventional NMR restraints and residual dipolar couplings. The cbEGF domains have an elongated, rod-like arrangement, as predicted. The new structure allows a detailed assessment of the consequences of mutations associated with familial hypercholesterolaemia to be made.Conclusions:The validation of the conserved arrangement of EGF domains in functionally distinct proteins has important implications for structural genomics, since multiple tandem cbEGF pairs have been identified in many essential proteins that are implicated in human disease. Our results provide the means to use homology modeling to probe structure-function relationships in this diverse family of proteins and may hold the potential for the design of novel diagnostics and therapies in the future.
DOI：
--
发表时间：
1989-12
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
D. Russell;Michael S. Brown;Joseph L. Goldstein
通讯作者：
D. Russell;Michael S. Brown;Joseph L. Goldstein
DOI：
10.1016/s0021-9258(18)37702-0
发表时间：
1988-09
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
V. Esser;L. Limbird;M. Brown;J. Goldstein;D. Russell
通讯作者：
V. Esser;L. Limbird;M. Brown;J. Goldstein;D. Russell
影响因子：
56.9
作者：
SUDHOF, TC;GOLDSTEIN, JL;RUSSELL, DW
通讯作者：
RUSSELL, DW