The SERCA Residue Glu340 Mediates Interdomain Communication That Guides Ca 2+ Transport

Significance We present a crystal structure, functional data, and molecular dynamics (MD) simulations of the sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) mutant E340A. The mutation slows Ca 2+ -binding kinetics, and the structural differences between wild type and E340A indicate that the mutation disrupts a central interdomain “communication hub” governing Ca 2+ binding/dissociation. MD simulations reveal altered dynamics in regions mediating Ca 2+ occlusion, a critical step in SERCA’s alternating access mechanism. The mutation stabilizes a more occluded state of the Ca 2+ sites. The strict conservation of Glu340 among P-type ATPases is the result of its critical role in interdomain communication between the cytosolic headpiece and the transmembrane domain, ensuring a delicate balance between dynamics of ion binding, occlusion, and release—key steps in the transport process.