LOCATIONS OF CALMODULIN AND FK506-BINDING PROTEIN ON THE 3-DIMENSIONAL ARCHITECTURE OF THE SKELETAL-MUSCLE RYANODINE RECEPTOR

Isolated skeletal muscle ryanodine receptors (RyRs) complexed with the modulatory ligands, calmodulin (CaM) or 12-kDa FK506-binding protein (FKBP12), have been characterized by electron cryomicroscopy and three -dimensional reconstruction, RyRs are composed of 4 large subunits (mo lecular mass 565 kDa) that assemble to form a 4-fold symmetric complex that, architecturally, comprises two major substructures, a large (ap proximate to 80% of the total mass) cytoplasmic assembly and a smaller transmembrane assembly. Both CaM and FKBP12 bind to the cytoplasmic a ssembly at sites that are 10 and 12 nm, respectively, from the putativ e entrance to the transmembrane ion channel, FKBP12 binds along the ed ge of the square shaped cytoplasmic assembly near the face that intera cts in vivo with the sarcolemma/transverse tubule membrane system, whe reas CaM binds within a cleft that faces the junctional face of the sa rcoplasmic reticulum membrane at the triad junction. Both ligands inte ract with a domain that connects directly to a cytoplasmic extension o f the transmembrane assembly of the receptor, and thus might cause str uctural changes in the domain which in turn modulate channel gating.