The Phox Homology (PX) domain-dependent, 3-phosphoinositide-mediated association of sorting nexin-1 with an early sorting endosomal compartment is required for its ability to regulate epidermal growth factor receptor degradation
The Phox Homology (PX) domain-dependent, 3-phosphoinositide-mediated association of sorting nexin-1 with an early sorting endosomal compartment is required for its ability to regulate epidermal growth factor receptor degradation
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DOI：
10.1074/jbc.m206986200
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发表时间：
2002-12-13
影响因子：
4.8
通讯作者：
Cullen, PJ
中科院分区：
文献类型：
--
作者：
Cozier, GE;Carlton, J;Cullen, PJ
最近的研究表明，phox同源（PX）结构域作为磷酸肌醇结合基序。研究的大多数PX结构域显示与磷脂酰肌醇3-单磷酸（Ptdlns（3）P）结合，这种结合允许宿主蛋白定位于内吞途径的膜。然而，一个问题是PX结构域是否可以具有替代的磷酸肌醇结合特异性，其可以将其宿主蛋白靶向不同的亚细胞区室或允许其通过除了PtdIns（3）P之外的磷酸肌醇进行变构调节。已经报道了分选连接蛋白1（SNX 1）的PX结构域特异性结合磷脂酰肌醇3，4，5-三磷酸（PtdIns（3，4，5）P-3）（Zhong，Q.，拉扎尔角美国，Tronchere，H.，佐藤，T.，Meerloo，T.，Yeo，M.，松阳，Z.，Emr，S. D、和Gill，G. N.等人（2002）Proc. Acad. Sci.联合S. A. 99，6767 -6772）。在本研究中，我们已经表明，尽管SNX 1在蛋白质：脂质覆盖测定中结合PtdIns（3，4，5）P-3，但在基于脂质体的测定中，观察到与PtdIns（3）P和磷脂酰肌醇3，5-二磷酸（PtdIns（3，5）P-2）结合，但不与PtdIns（3，4，5）P-3结合。为了说明PtdIns（3，4，5）P-3结合的重要性，我们在质膜PtdIns（3，4，5）P-3水平显著升高的条件下检测了SNX 1的亚细胞定位。在这些条件下，我们未能观察到SNX 1与该膜的缔合。然而，与PtdIns（3）P和PtdIns（3，5）P-2的结合具有更大的生理意义一致的是，观察到SNX 1与早期内体区室的结合依赖于3-磷酸肌醇结合PX结构域和该区室上PtdIns（3）P的存在。最后，SNX 1的染色体结合对于其调节内化的表皮生长因子受体靶向溶酶体降解的能力是重要的。
Recent studies have shown that phox homology (PX) domains act as phosphoinositide-binding motifs. The majority of PX domains studied show binding to phosphatidylinositol 3-monophosphate (Ptdlns(3)P), an association that allows the host protein to localize to membranes of the endocytic pathway. One issue, however, is whether PX domains may have alternative phosphoinositide binding specificities that could target their host protein to distinct subcellular compartments or allow their allosteric regulation by phosphoinositides other than PtdIns(3)P. It has been reported that the PX domain of sorting nexin 1 (SNX1) specifically binds phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P-3) (Zhong, Q., Lazar, C. S., Tronchere, H., Sato, T., Meerloo, T., Yeo, M., Songyang, Z., Emr, S. D., and Gill, G. N. (2002) Proc. Natl. Acad. Sci. U. S. A. 99,6767-6772). In the present study, we have shown that whereas SNX1 binds PtdIns(3,4,5)P-3 in protein:lipid overlay assays, in liposomes-based assays, binding is observed to PtdIns(3)P and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P-2) but not to PtdIns(3,4,5)P-3. To address the significance of PtdIns(3,4,5)P-3 binding, we examined the subcellular localization of SNX1 under conditions in which plasma membrane PtdIns(3,4,5)P-3 levels were significantly elevated. Under these conditions, we failed to observe association of SNX1 with this membrane. However, consistent with the binding to PtdIns(3)P and PtdIns(3,5)P-2 being of more physiological significance was the observation that the association of SNX1 with an early endosomal compartment was dependent on a 3-phosphoinositide-binding PX domain and the presence of PtdIns(3)P on this compartment. Finally, we somal association of SNX1 is important for its ability to regulate the targeting of internalized epidermal growth factor receptor for lysosomal degradation.