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Vol. 16, Issue 4, 2049-2057, April 2005
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* Departments of Medicine and Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0650;
Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, United Kingdom
Submitted June 22, 2004;
Accepted January 11, 2005
Monitoring Editor: Suzanne Pfeffer
The sorting nexin (SNX) family of proteins is characterized by sequence-related phox homology (PX) domains. A minority of PX domains bind with high affinity to phosphatidylinositol 3-phosphate [PI(3)P], whereas the majority of PX domains exhibit low affinity that is insufficient to target them to vesicles. SNX1 is located on endosomes, but its low affinity PX domain fails to localize in vivo. The NMR structure of the PX domain of SNX1 reveals an overall fold that is similar to high-affinity PX domains. However, the phosphatidylinositol (PI) binding pocket of the SNX1 PX domain is incomplete; regions of the pocket that are well defined in high-affinity PX domains are highly mobile in SNX1. Some of this mobility is lost upon binding PI(3)P. The C-terminal domain of SNX1 is a long helical dimer that localizes to vesicles but not to the early endosome antigen-1–containing vesicles where endogenous SNX1 resides. Thus, the obligate dimerization of SNX1 that is driven by the C-terminal domain creates a high-affinity PI binding species that properly targets the holo protein to endosomes.
These authors contributed equally to this study.
Address correspondence to: Gordon N. Gill (ggill{at}ucsd.edu) or Jonathan P. Waltho (j.waltho{at}sheffield.ac.uk).
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