Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains
Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains
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DOI：
10.1016/s1097-2765(00)00037-x
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发表时间：
2000-08-01
期刊：
影响因子：
16
通讯作者：
Lemmon, MA
中科院分区：
文献类型：
--
作者：
Ferguson, KM;Kavran, JM;Lemmon, MA
Pleckstrin同源结构域（PH）是在细胞信号传导的许多蛋白质中发现的大约120个氨基酸的蛋白质模块。某些PH结构域通过与激动剂刺激的磷酸肌肽3-激酶（PI 3-Ks）产生的脂质第二信使的强烈和特异性结合，驱动其宿主蛋白的信号依赖性膜募集。我们描述了两种不同PH域结合到Ins(1,3,4,5)P-4的x射线晶体结构，Ins(1,3,4,5)P-4是PI 3- k主要产物PtdIns(3,4,5)P-3的头基。其中一个PH结构域（来自Grp1）是PtdIns(3,4,5)P-3特异性的，而另一个（来自DAPP1/PHISH）强烈结合Ptdlns(3,4,5)P-3及其5'-去磷酸化产物Ptdlns(3,4)P-2。两种结构的比较解释了两种PH结构域不同的磷酸肌苷特异性，并使我们能够预测未表征的PH结构域的3-磷酸肌苷选择性。
Pleckstrin homology (PH) domains are protein modules of around 120 amino acids found in many proteins involved in cellular signaling. Certain PH domains drive signal-dependent membrane recruitment of their host proteins by binding strongly and specifically to lipid second messengers produced by agonist-stimulated phosphoinositide 3-kinases (PI 3-Ks). We describe X-ray crystal structures of two different PH domains bound to Ins(1,3,4,5)P-4, the head group of the major PI 3-K product PtdIns(3,4,5)P-3. One of these PH domains (from Grp1) is PtdIns(3,4,5)P-3 specific, while the other (from DAPP1/PHISH) binds strongly to both Ptdlns(3,4,5)P-3 and its 5'-dephosphorylation product, Ptdlns(3,4)P-2. Comparison of the two structures provides an explanation for the distinct phosphoinositide specificities of the two PH domains and allows us to predict the 3-phosphoinositide selectivity of uncharacterized PH domains.