Ca2+ binding to site I of the cardiac Ca2+ pump is sufficient to dissociate phospholamban.

The Journal of Biological Chemistry
Zhenhui ChenLarry R Jones

Abstract

Phospholamban (PLB) inhibits the activity of SERCA2a, the Ca(2+)-ATPase in cardiac sarcoplasmic reticulum, by decreasing the apparent affinity of the enzyme for Ca(2+). Recent cross-linking studies have suggested that PLB binding and Ca(2+) binding to SERCA2a are mutually exclusive. PLB binds to the E2 conformation of the Ca(2+)-ATPase, preventing formation of E1, the conformation that binds two Ca(2+) (at sites I and II) with high affinity and is required for ATP hydrolysis. Here we determined whether Ca(2+) binding to site I, site II, or both sites is sufficient to dissociate PLB from the Ca(2+) pump. Seven SERCA2a mutants with amino acid substitutions at Ca(2+)-binding site I (E770Q, T798A, and E907Q), site II (E309Q and N795A), or both sites (D799N and E309Q/E770Q) were made, and the effects of Ca(2+) on N30C-PLB cross-linking to Lys(328) of SERCA2a were measured. In agreement with earlier reports with the skeletal muscle Ca(2+)-ATPase, none of the SERCA2a mutants (except E907Q) hydrolyzed ATP in the presence of Ca(2+); however, all were phosphorylatable by P(i) to form E2P. Ca(2+) inhibition of E2P formation was observed only in SERCA2a mutants retaining site I. In cross-linking assays, strong cross-linking between N30C-PL...Continue Reading

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Citations

Aug 13, 2011·The Journal of Biological Chemistry·Philip BidwellSeth L Robia
Mar 20, 2012·The Journal of Biological Chemistry·Delaine K CeholskiHoward S Young
Jan 31, 2013·The Journal of Biological Chemistry·Przemek A GorskiHoward S Young
Oct 22, 2013·Biophysical Journal·Sandeep PallikkuthSeth L Robia
Apr 12, 2015·Biophysical Journal·L Michel Espinoza-FonsecaDavid D Thomas
Mar 13, 2012·Biochemical and Biophysical Research Communications·Simon J GruberDavid D Thomas
May 13, 2014·Biochemical and Biophysical Research Communications·Xiaoqiong Dong, David D Thomas
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