Cockcroft Shamshad, Garner Kathryn
Dept. of Neuroscience, Physiology and Pharmacology, Division of Biosciences, University College London, London WC1E 6JJ, UK.
Adv Biol Regul. 2013 Sep;53(3):280-91. doi: 10.1016/j.jbior.2013.07.007. Epub 2013 Jul 21.
The hallmark of mammalian phosphatidylinositol transfer proteins (PITPs) is to transfer phosphatidylinositol between membrane compartments. In the mammalian genome, there are three genes that code for soluble PITP proteins, PITPα, PITPβ and RdgBβ and two genes that code for membrane-associated multi-domain proteins (RdgBαI and II) containing a PITP domain. PITPα and PITPβ constitute Class I PITPs whilst the RdgB proteins constitute Class II proteins based on sequence analysis. The PITP domain of both Class I and II can sequester one molecule of phosphatidylinositol (PI) in its hydrophobic cavity. Therefore, in principle, PITPs are therefore ideally poised to couple phosphatidylinositol delivery to the PI kinases for substrate provision for phospholipases C during cell activation. Since phosphatidylinositol (4,5)bisphosphate plays critical roles in cells, particularly at the plasma membrane, where it is a substrate for both phospholipase C and phosphoinositide-3-kinases as well as required as an intact lipid to regulate ion channels and the actin cytoskeleton, homeostatic mechanisms to maintain phosphatidylinositol(4,5)bisphosphate levels are vital. To maintain phosphatidylinositol levels, phospholipase C activation inevitably leads to the resynthesis of PI at the endoplasmic reticulum where the enzymes are located. Phosphatidic acid generated at the plasma membrane during phospholipase C activation needs to move to the ER for conversion to PI and here we provide evidence that Class II PITPs are also able to bind and transport phosphatidic acid. Thus RdgB proteins could couple PA and PI transport bidirectionally during phospholipase C signalling.
哺乳动物磷脂酰肌醇转移蛋白（PITPs）的标志是在膜区室之间转移磷脂酰肌醇。在哺乳动物基因组中，有三个基因编码可溶性PITP蛋白，即PITPα、PITPβ和RdgBβ，还有两个基因编码含有PITP结构域的膜相关多结构域蛋白（RdgBαI和II）。根据序列分析，PITPα和PITPβ构成I类PITPs，而RdgB蛋白构成II类蛋白。I类和II类的PITP结构域都能在其疏水腔内螯合一分子磷脂酰肌醇（PI）。因此，原则上，PITPs非常适合在细胞激活过程中将磷脂酰肌醇传递给PI激酶，为磷脂酶C提供底物。由于磷脂酰肌醇（4,5）二磷酸在细胞中起着关键作用，特别是在质膜上，它是磷脂酶C和磷酸肌醇-3-激酶的底物，也是调节离子通道和肌动蛋白细胞骨架所需的完整脂质，因此维持磷脂酰肌醇（4,5）二磷酸水平的稳态机制至关重要。为了维持磷脂酰肌醇水平，磷脂酶C的激活不可避免地导致内质网（酶所在的位置）处PI的重新合成。磷脂酶C激活过程中在质膜产生的磷脂酸需要转移到内质网转化为PI，在这里我们提供证据表明II类PITPs也能够结合和转运磷脂酸。因此，RdgB蛋白可以在磷脂酶C信号传导过程中双向偶联PA和PI的运输。
