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Title: Structural basis for the high Ca2+ affinity of the ubiquitous SERCA2b Ca2+ pump
Authors: Vandecaetsbeek, Ilse ×
Trekels, Mieke
De Maeyer, Marc
Ceulemans, Hugo
Lescrinier, Eveline
Raeymaekers, Luc
Wuytack, Frank
Vangheluwe, Peter #
Issue Date: Nov-2009
Publisher: National Academy of Sciences
Series Title: Proceedings of the National Academy of Sciences of the United States of America vol:106 issue:44 pages:18533-18538
Abstract: Sarco(endo) plasmic reticulum Ca2+ ATPase (SERCA) Ca2+ transporters pump cytosolic Ca2+ into the endoplasmic reticulum, maintaining a Ca2+ gradient that controls vital cell functions ranging from proliferation to death. To meet the physiological demand of the cell, SERCA activity is regulated by adjusting the affinity for Ca2+ ions. Of all SERCA isoforms, the housekeeping SERCA2b isoform displays the highest Ca2+ affinity because of a unique C-terminal extension (2b-tail). Here, an extensive structure-function analysis of SERCA2b mutants and SERCA1a2b chimera revealed how the 2b-tail controls Ca2+ affinity. Its transmembrane (TM) segment (TM11) and luminal extension functionally cooperate and interact with TM7/TM10 and luminal loops of SERCA2b, respectively. This stabilizes the Ca2+-bound E1 conformation and alters Ca2+-transport kinetics, which provides the rationale for the higher apparent Ca2+ affinity. Based on our NMR structure of TM11 and guided by mutagenesis results, a structural model was developed for SERCA2b that supports the proposed 2b-tail mechanism and is reminiscent of the interaction between the alpha- and beta-subunits of Na+, K+-ATPase. The 2b-tail interaction site may represent a novel target to increase the Ca2+ affinity of malfunctioning SERCA2a in the failing heart to improve contractility.
ISSN: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Medicinal Chemistry (Rega Institute)
Biochemistry, Molecular and Structural Biology Section
Laboratory of Cellular Transport Systems
Faculty of Medicine - miscellaneous
× corresponding author
# (joint) last author

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