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Molecular insights into SERCA regulation by endogenous peptide modulators Open Access


Other title
Type of item
Degree grantor
University of Alberta
Author or creator
Gorski, Przemyslaw A
Supervisor and department
Young, Howard (Biochemistry)
Examining committee member and department
Glover, Mark (Biochemistry)
Cordat, Emmanuelle (Physiology)
Graham, Todd (Biological Sciences, Vanderbilt University)
Michalak, Marek (Biochemistry)
Department of Biochemistry

Date accepted
Graduation date
Doctor of Philosophy
Degree level
In human cells, oscillations in calcium concentration serve as a mechanism for controlling a variety of physiological processes including muscle contraction and relaxation. The sarcoplasmic reticulum (SR) is a calcium storage organelle in muscle cells that contains a calcium pump (SERCA) required for the reuptake of calcium into the SR for muscle relaxation. The activity of SERCA is tightly regulated through reversible interactions with the short integral membrane proteins, phospholamban (PLN) and sarcolipin (SLN). Defects in the regulation of SERCA are a central determinant in end-stage heart failure. Consequently, the regulatory mechanisms imposed by PLN and SLN could have clinical implications for heart and skeletal muscle diseases. This thesis aims to provide functional insights into regulatory complexes formed between SERCA and its endogenous peptide modulators. We sought to examine how SERCA activity is regulated by tissue-specific endogenous peptide modulators in order to meet the physiological needs of a specific cell type. Using alanine-scanning mutagenesis and chimeric PLN-SLN constructs, we identified the highly conserved luminal extension of SLN as a functionally important and transferrable domain that is a primary determinant for SERCA inhibition. Based on these findings, we concluded that SLN uses an inhibitory mechanism that is distinct from that of PLN. We also studied the ability of zebrafish phospholamban-like protein (zfPLN) to regulate SERCA. Functional analysis of zfPLN revealed that despite the high sequence diversity between zebrafish and human PLN, as well as the presence of a unique zfPLN luminal extension, zfPLN has inhibitory properties that are similar to human PLN. Finally, we examined the role of the 11th transmembrane segment (TM11) of the ubiquitous SERCA2b in calcium transport. Our studies revealed that TM11 is a distinct and highly conserved functional region of SERCA2b that serves as a genuine regulator of the calcium pump. Combined, the results provide novel insights into the different mechanisms of SERCA regulation by endogenous peptide modulators.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Gorski, P. A., Glaves, J. P., Vangheluwe, P., and Young, H. S. (2013) Sarco(endo)plasmic reticulum calcium ATPase (SERCA) inhibition by sarcolipin is encoded in its luminal tail. The Journal of biological chemistry 288, 8456-8467Gorski, P. A., Trieber, C. A., Lariviere, E., Schuermans, M., Wuytack, F., Young, H. S., and Vangheluwe, P. (2012) Transmembrane helix 11 is a genuine regulator of the endoplasmic reticulum Ca2+ pump and acts as a functional parallel of beta-subunit on alpha-Na+,K+-ATPase. The Journal of biological chemistry 287, 19876-19885

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