Binding of internalized receptors to the PDZ domain of GIPC/synectin recruits myosin VI to endocytic vesicles.
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.
Naccache
Samia N
SN
Section of Cell and Developmental Biology, Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093, USA.
Hasson
Tama
T
Horowitz
Arie
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D008024:Ligands; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018995:Myosin Heavy Chains / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D022161:Transport Vesicles / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C115271:Gipc1 protein, mouse; D008024:Ligands; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D009479:Neuropeptides; C089785:myosin VI; D018995:Myosin Heavy Chains