Reexamination of the role of the leucine/isoleucine zipper residues of phospholamban in inhibition of the Ca2+ pump of cardiac sarcoplasmic reticulum

Razvan L. Cornea, Joseph M. Autry, Zhenhui Chen, Larry Jones

Research output: Contribution to journalArticle

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Abstract

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 α-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.

Original languageEnglish
Pages (from-to)41487-41494
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number52
DOIs
StatePublished - Dec 29 2000

Fingerprint

Leucine Zippers
Isoleucine
Fasteners
Sarcoplasmic Reticulum
Leucine
Pumps
Monomers
phospholamban
Phosphoproteins
Amino Acid Substitution
Substitution reactions
Membranes
Amino Acids

ASJC Scopus subject areas

  • Biochemistry

Cite this

Reexamination of the role of the leucine/isoleucine zipper residues of phospholamban in inhibition of the Ca2+ pump of cardiac sarcoplasmic reticulum. / Cornea, Razvan L.; Autry, Joseph M.; Chen, Zhenhui; Jones, Larry.

In: Journal of Biological Chemistry, Vol. 275, No. 52, 29.12.2000, p. 41487-41494.

Research output: Contribution to journalArticle

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