Signal-dependent membrane targeting by pleckstrin homology (PH) domains.
Signal-dependent membrane targeting by pleckstrin homology (PH) domains.
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DOI：
10.1042/bj3500001
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发表时间：
2000-08
期刊：
影响因子：
--
通讯作者：
M. Lemmon;K. Ferguson
中科院分区：
文献类型：
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作者：
M. Lemmon;K. Ferguson
Pleckstrin Homology(PH)结构域是由大约120个氨基酸组成的小蛋白质模块，存在于许多蛋白质中，参与细胞信号传递、细胞骨架重排和其他过程。虽然已经提出了几种不同的蛋白质配体来表达PH结构域，但到目前为止，它们唯一明确的生理功能是与膜上的磷脂酰肌醇结合。磷脂酶C-Delta(1)的PH结构域与PtdIns(4，5)P(2)及其头基特异结合，已成为研究细胞内PtdIns(4，5)P(2)功能的有效工具。最近的研究表明，PH结构域的一个子集识别激动剂刺激的磷脂酰肌醇3-激酶的产物。这些PH结构域与绿色荧光蛋白的融合使它们能够戏剧性地展示出它们独立的能力，推动它们的宿主蛋白依赖于信号向质膜募集。我们讨论了这种3-磷酸肌醇识别的结构基础，以及它在细胞信号传递中所起的作用。与磷脂酰肌醇特异结合的pH结构域只占已知结构域的一小部分(可能15%)，这就提出了剩余85%的PH结构域的生理作用的问题。大多数(如果不是全部)PH结构域与磷脂酰肌醇结合很弱且非特异性。对Dynamin-1的研究表明，其PH结构域的寡聚化可能是驱动膜结合的重要因素。我们讨论了对磷脂酰肌醇具有低亲和力的PH结构域膜靶向性可能是由其低聚体状态的改变以及膜结合亲和力的改变所驱动的。
Pleckstrin homology (PH) domains are small protein modules of around 120 amino acids found in many proteins involved in cell signalling, cytoskeletal rearrangement and other processes. Although several different protein ligands have been proposed for PH domains, their only clearly demonstrated physiological function to date is to bind membrane phosphoinositides. The PH domain from phospholipase C-delta(1) binds specifically to PtdIns(4,5)P(2) and its headgroup, and has become a valuable tool for studying cellular PtdIns(4,5)P(2) functions. More recent developments have demonstrated that a subset of PH domains recognizes the products of agonist-stimulated phosphoinositide 3-kinases. Fusion of these PH domains to green fluorescent protein has allowed dramatic demonstrations of their independent ability to drive signal-dependent recruitment of their host proteins to the plasma membrane. We discuss the structural basis for this 3-phosphoinoistide recognition and the role that it plays in cellular signalling. PH domains that bind specifically to phosphoinositides comprise only a minority (perhaps 15%) of those known, raising questions as to the physiological role of the remaining 85% of PH domains. Most (if not all) PH domains bind weakly and non-specifically to phosphoinositides. Studies of dynamin-1 have indicated that oligomerization of its PH domain may be important in driving membrane association. We discuss the possibility that membrane targeting by PH domains with low affinity for phosphoinositides could be driven by alteration of their oligomeric state and thus the avidity of their membrane binding.