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Please use this identifier to cite or link to this item: http://hdl.handle.net/1813/7893
Title: Structure of BAR and PX Domains of Sorting Nexin 9 Reveals Cooperativity in Membrane Binding
Authors: Kaan, Hung Yi Kristal
Issue Date: 6-Jul-2007
Abstract: Sorting nexin 9 (SNX9) belongs to a larger family of BAR-domain containing proteins. It is characterized by an N-terminal Src homology 3 (SH3) domain, a phox homology (PX) domain, and a Bin/Amphiphysin/Rvs-homology (BAR) domain. Together with clathrin and dynamin, it functions mainly in the endocytic pathway to sort proteins. SNX9 has also been shown to regulate receptor-mediated endocytosis of epidermal growth factor receptor (EGFR), by its interaction with Activated Cdc42-associated kinase-2 (ACK2), thus implicating a role for SNX9 in signal transduction. Although the main cellular functions of SNX9 have been brought to light, little is known about the molecular mechanism by which this multi-domain protein participates in endocytosis and signaling. It is also unclear if and how the protein is regulated. In order to understand the interactions between the various domains of SNX9, we have crystallized and solved the structure of a shorter construct of SNX9 (here after called SNX9PX-BAR), which consists of only the PX and BAR domains. By analyzing this multi-domain structure and by conducting lipid- and vesicle-binding assays, we are able to gain a better understanding of how the two domains interact to influence the membrane binding ability of SNX9. Our analysis of the structure of SNX9PX-BAR shows a dimeric BAR domain that is moderately curved. The BAR domain forms stable dimers via mainly hydrophobic interactions on the membrane surface. Membrane binding is most likely driven by electrostatic interactions between the PX-BAR domain and the negatively-charged plasma membrane. In addition, the PX domain of SNX9 shows high and specific binding affinity to PI(3)P, which is in high concentrations in early endosomes. Therefore, we propose that SNX9 might be localized to both the plasma membrane and the early endosomes to participate in endocytosis and sorting of vesicles.
URI: http://hdl.handle.net/1813/7893
Appears in Collections:College of Agriculture and Life Sciences Honors Theses

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