title: The role of phosphorylation on the structure and dynamics of phospholamban: a model from molecular simulations.
abstract: Phospholamban (PLB) is a small membrane protein that regulates the activity of the calcium ATP-ase in the cardiac, slow-twitch, and smooth muscle sarcoplasmic reticulum through the reversible phosphorylation of Ser16. We present here a comparative molecular dynamics study of unmodified and phosphorylated PLB immersed in a phospholipid membrane. The study has been performed under different ionic strength conditions, using the NMR structures of two PLB variants determined in mixed organic solvent and dodecylphosphocholine micelles. The simulations indicate that all PLB forms studied display a highly dynamic behavior of the N-terminal cytoplasmic moiety, with a decrease of its helical content in the phosphorylated forms. The cytoplasmic domain undergoes large collective motions sampling conformations parallel as well as perpendicular to the membrane surface in all the simulations. The transmembrane domain retains a tightly folded helical conformation with a small tilt with respect to the membrane plane probably induced by the presence of Asn30 and Asn34 within the hydrophobic environment. Furthermore, the phosphoric group on Ser16 establishes transient electrostatic interactions with the phospholipid heads. We propose a model in which phosphorylation diminishes the probability of interactions of PLB with residues near Lys400 in the SERCA pump, thus relieving its inhibition.
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM),Via Orus 2, 35129, Padova, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Pantano
authors.forename: Ernesto
authors.initials: E
authors.lastname: Carafoli
mesh_terms: D001216:Asparagine / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D003198:Computer Simulation; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012694:Serine / Q000235:genetics / Q000378:metabolism; D014867:Water / Q000737:chemistry / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D001216:Asparagine; D002135:Calcium-Binding Proteins; D012694:Serine; D014867:Water; D000099211:Phospholamban