期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 275, 期 52, 页码 41487-41494出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M008195200
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资金
- NHLBI NIH HHS [HL49428] Funding Source: Medline
Phospholamban is a small phosphoprotein inhibitor of the Ca2+-pump in cardiac sarcoplasmic reticulum, which shows a distinct oligomeric distribution between monomers and homopentamers that are stabilized through Leu/Ile zipper interactions. A two-faced model of phospholamban inhibition of the Ca2+-pump was proposed, in which the Leu/Ile zipper residues located on one face of the transmembrane alpha -helix regulate the pentamer to monomer equilibrium, whereas residues on the other face of the helix bind to and inhibit the pump, Here we tested this two-faced model of phospholamban action by analyzing the functional effects of a new series of Leu/Ile zipper mutants. Pentameric stabilities of the mutants were quantified at different SDS concentrations. We show that several phospholamban mutants with hydrophobic amino acid substitutions at the Leu/Ile zipper region retain the ability to form pentamers but at the same time give the same or even stronger (i.e. L37I-PLB) inhibition of the Ca2+-pump than do mutants that are more completely monomeric. Steric constraints prevent the Leu/Ile zipper residues sequestered in the interior of the phospholamban pentamer from binding to the Ca2+-pump, leading. to the conclusion that the zipper residues access the pump from the phospholamban monomer, which is the active inhibitory species. A modified model of phospholamban transmembrane domain action is proposed, in which the membrane span of the phospholamban monomer maintains contacts with the Ca2+-pump around most of its circumference, including residues located in the Leu/Ile zipper region.
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