title: FKBP12 binds the inositol 1,4,5-trisphosphate receptor at leucine-proline (1400-1401) and anchors calcineurin to this FK506-like domain.
abstract: The immunophilin FKBP12 is one of the most abundant and conserved proteins in biology. It is the primary receptor for the immunosuppressant actions of the drug FK506 in whose presence FKBP12 binds to and inhibits calcineurin, disrupting interleukin formation in lymphocytes. The physiologic functions of FKBP12 are less clear, although the protein has been demonstrated to physiologically interact with the inositol 1,4,5-trisphosphate receptor (IP3R), the ryanodine receptor, and the type 1 transforming growth factor beta receptor. We now report that FKBP12 binds the IP3R at residues 1400-1401, a leucyl-prolyl dipeptide epitope that structurally resembles FK506. We further demonstrate that binding to IP3R at this site enables FKBP12 to interact with calcineurin, presumably to anchor the phosphatase to IP3R and modulate the receptor's phosphorylation status. We propose that FK506 promotes an FKBP12-calcineurin interaction by mimicking structurally similar dipeptide epitopes present within proteins that use FKBP12 to anchor calcineurin to the appropriate physiologic substrates.
authors.affiliation: Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Cameron
authors.forename: F C
authors.initials: FC
authors.lastname: Nucifora
authors.forename: E T
authors.initials: ET
authors.lastname: Fung
authors.forename: D J
authors.initials: DJ
authors.lastname: Livingston
authors.forename: R A
authors.initials: RA
authors.lastname: Aldape
authors.forename: C A
authors.initials: CA
authors.lastname: Ross
authors.forename: S H
authors.initials: SH
authors.lastname: Snyder
mesh_terms: D000595:Amino Acid Sequence; D019703:Calcineurin / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007930:Leucine / Q000378:metabolism*; D008969:Molecular Sequence Data; D011392:Proline / Q000378:metabolism*; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D016559:Tacrolimus / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins
chemical_list: D015220:Calcium Channels; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D011392:Proline; D019703:Calcineurin; D022021:Tacrolimus Binding Proteins; D007930:Leucine; D016559:Tacrolimus