Structural basis for the high Ca2+ affinity of the ubiquitous SERCA2b Ca2+ pump
| Autor: | Mieke Trekels, Eveline Lescrinier, Hugo Ceulemans, Peter Vangheluwe, Luc Raeymaekers, Marc De Maeyer, Frank Wuytack, Ilse Vandecaetsbeek |
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| Rok vydání: | 2009 |
| Předmět: |
Models
Molecular ca2+-atpase SERCA Calcium pump Molecular Sequence Data Biology Protein Structure Secondary Sarcoplasmic Reticulum Calcium-Transporting ATPases sarcoplasmic-reticulum ca2+-atpase Structure-Activity Relationship angstrom resolution Chlorocebus aethiops Enzyme Stability p-type atpase Animals functional differences Amino Acid Sequence Na+/K+-ATPase Binding site sodium-potassium pump phospholamban Ion transporter Multidisciplinary Binding Sites heart-failure Endoplasmic reticulum transient kinetic analyses crystal-structure ion transporter Biological Sciences Recombinant Proteins Phospholamban Protein Structure Tertiary dilated cardiomyopathy endoplasmic reticulum calcium-pump Kinetics darier-disease Biochemistry COS Cells P-type ATPase Biophysics Calcium Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 106(44) |
| ISSN: | 1091-6490 |
| Popis: | Sarco(endo)plasmic reticulum Ca 2+ ATPase (SERCA) Ca 2+ transporters pump cytosolic Ca 2+ into the endoplasmic reticulum, maintaining a Ca 2+ 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 Ca 2+ ions. Of all SERCA isoforms, the housekeeping SERCA2b isoform displays the highest Ca 2+ 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 Ca 2+ 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 Ca 2+ -bound E1 conformation and alters Ca 2+ -transport kinetics, which provides the rationale for the higher apparent Ca 2+ 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 α- and β-subunits of Na + ,K + -ATPase. The 2b-tail interaction site may represent a novel target to increase the Ca 2+ affinity of malfunctioning SERCA2a in the failing heart to improve contractility. |
| Databáze: | OpenAIRE |
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