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A more recent version of this article appeared on July 1, 2007
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Submitted on October 5, 2006
Revised on April 3, 2007
Accepted on April 26, 2007
*Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390; Department of Cell Biology and CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115; Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
Monitoring Editor: Sandra Schmid
Phosphatidylinositol 4 phosphate (PI4P) is highly enriched in the trans-Golgi network (TGN). Here we establish that PI4P is a key regulator of the recruitment of the GGA clathrin adaptor proteins (GGAs) to the TGN and that PI4P has a novel role in promoting their recognition of the ubiquitin (Ub) sorting signal. Knockdown of PI4KII
by RNA interference (RNAi), which depletes the TGN’s PI4P, impaired the recruitment of the GGAs to the TGN. GGAs bind PI4P primarily through their GAT domain, in a region called C-GAT which also binds Ub but not Arf1. We identified two basic residues in the GAT domain that are essential for PI4P binding in vitro and for the recruitment of GGAs to the TGN in vivo. Unlike wildtype GGA, GGA with mutated GATs failed to rescue the abnormal TGN phenotype of the GGA RNAi-depleted cells. These residues partially overlap with those that bind Ub, and PI4P increased the affinity of the GAT domain for Ub. Because the recruitment of clathrin adaptors and their cargoes to the TGN is mediated through a web of low affinity interactions, our results show that the dual roles of PI4P can promote specific GGA targeting and cargo recognition at the TGN.
These authors contributed equally to this work.
Address correspondence to:
Helen L. Yin (Helen.Yin{at}UTSouthwestern.edu)
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