Ca2+-dependent calmodulin binding to FcRn affects immunoglobulin G transport in the transcytotic pathway |
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Authors: | Dickinson Bonny L Claypool Steven M D'Angelo June A Aiken Martha L Venu Nanda Yen Elizabeth H Wagner Jessica S Borawski Jason A Pierce Amy T Hershberg Robert Blumberg Richard S Lencer Wayne I |
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Institution: | The Research Institute for Children, Children's Hospital, Department of Pediatrics, New Orleans, LA 70118, USA. |
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Abstract: | The Fcγ receptor FcRn transports immunoglobulin G (IgG) so as to avoid lysosomal degradation and to carry it bidirectionally across epithelial barriers to affect mucosal immunity. Here, we identify a calmodulin-binding site within the FcRn cytoplasmic tail that affects FcRn trafficking. Calmodulin binding to the FcRn tail is direct, calcium-dependent, reversible, and specific to residues comprising a putative short amphipathic α-helix immediately adjacent to the membrane. FcRn mutants with single residue substitutions in this motif, or FcRn mutants lacking the cytoplasmic tail completely, exhibit a shorter half-life and attenuated transcytosis. Chemical inhibitors of calmodulin phenocopy the mutant FcRn defect in transcytosis. These results suggest a novel mechanism for regulation of IgG transport by calmodulin-dependent sorting of FcRn and its cargo away from a degradative pathway and into a bidirectional transcytotic route. |
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