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Binding of Internalized Receptors to the PDZ Domain of GIPC/Synectin Recruits Myosin VI to Endocytic Vesicles
Samia N. Naccache, Tama Hasson and Arie Horowitz
Proceedings of the National Academy of Sciences of the United States of America
Vol. 103, No. 34 (Aug. 22, 2006), pp. 12735-12740
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/30051078
Page Count: 6
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Myosin VI (myo6) is the only actin-based molecular motor that translocates along actin filaments toward the minus end. Myo6 participates in two steps of endocytic trafficking; it is recruited to both clathrin-coated pits and to ensuing uncoated endocytic vesicles (UCV). Although there is evidence suggesting that the PDZ adaptor protein GIPC/synectin is involved in the association of myo6 with UCV, the recruitment mechanism is unknown. We show that GIPC/synectin is required for both internalization of cell surface receptors and for coupling of myo6 to UCV. This coupling occurs via a mechanism wherein engagement of the GIPC/synectin PDZ domain by C termini of internalized receptors facilitates in trans myo6 binding to the GIPC/synectin C terminus located outside of the PDZ domain. Analysis of megalin, a prototypical GIPC/ synectin-binding receptor, revealed that deletion of its PDZ-binding motif drastically reduced GIPC/synectin and myo6 recruitment to UCV. Furthermore, interaction with GIPC/synectin was required for megalin's function, as megalin was mistargeted in the renal proximal tubules of GIPC/synectin-null mice and these mice exhibited proteinuria, a condition consistent with defective megalin trafficking.
Proceedings of the National Academy of Sciences of the United States of America © 2006 National Academy of Sciences