title: Ca2+-dependent calmodulin binding to FcRn affects immunoglobulin G transport in the transcytotic pathway.
abstract: The Fcgamma 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 alpha-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.
authors.affiliation: The Research Institute for Children, Children's Hospital, Department of Pediatrics, New Orleans, LA 70118, USA.
authors.forename: Bonny L
authors.initials: BL
authors.lastname: Dickinson
authors.forename: Steven M
authors.initials: SM
authors.lastname: Claypool
authors.forename: June A
authors.initials: JA
authors.lastname: D'Angelo
authors.forename: Martha L
authors.initials: ML
authors.lastname: Aiken
authors.forename: Nanda
authors.initials: N
authors.lastname: Venu
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Yen
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Wagner
authors.forename: Jason A
authors.initials: JA
authors.lastname: Borawski
authors.forename: Amy T
authors.initials: AT
authors.lastname: Pierce
authors.forename: Robert
authors.initials: R
authors.lastname: Hershberg
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.forename: Wayne I
authors.initials: WI
authors.lastname: Lencer
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D002460:Cell Line; D016764:Cell Polarity; D004285:Dogs; D004705:Endocytosis; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011961:Receptors, Fc / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002147:Calmodulin; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; D002118:Calcium; C100688:Fc receptor, neonatal