Modeling of the Inhibitory Interaction of Phospholamban with the Ca2+ATPase

The inhibitory interaction of phospholamban (PLN) with the sarco(endo)plasmic reticulum Ca2+ATPase isoform 1 (SERCA1a) was modeled on the basis of several constraints which included (i) spontaneous formation of SS-bridges between mutants L321C in transmembrane helix 4 (M4) of SERCA1a and N27C in PLN...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2003-01, Vol.100 (2), p.467-472
Main Authors: Toyoshima, Chikashi, Asahi, Michio, Sugita, Yuji, Khanna, Reena, Tsuda, Takeo, MacLennan, David H.
Format: Article
Language:English
Subjects:
Adenosine triphosphatases
Amino Acid Sequence
Amino acids
Atomic interactions
Biological Sciences
Calcium
Calcium-Binding Proteins - chemistry
Calcium-Transporting ATPases - antagonists & inhibitors
Calcium-Transporting ATPases - chemistry
Cell Membrane - chemistry
Cytosol - chemistry
Genomics
Humans
Modeling
Models, Molecular
Molecular dynamics
Molecular interactions
Molecular Sequence Data
Molecules
Monomers
Mutagenesis
Mutation
Phosphorylation
Protein Structure, Secondary
Sarcoplasmic Reticulum Calcium-Transporting ATPases
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Summary:The inhibitory interaction of phospholamban (PLN) with the sarco(endo)plasmic reticulum Ca2+ATPase isoform 1 (SERCA1a) was modeled on the basis of several constraints which included (i) spontaneous formation of SS-bridges between mutants L321C in transmembrane helix 4 (M4) of SERCA1a and N27C in PLN and between V89C (M4) and V49C (PLN); (ii) definition of the face of the PLN transmembrane helix that interacts with SERCA; (iii) cross-linking between Lys-3 of PLN and Lys-397 and Lys-400 of SERCA2a. The crystal structure of SERCA1a in the absence of Ca2+, which binds PLN, was used as the structure into which an atomic model of PLN was built. PLN can fit into a transmembrane groove formed by the juxtaposition of M2, the upper part of M4, M6, and M9. In the SERCA1a structure with bound Ca2+, this groove is closed, accounting for the ability of Ca2+to disrupt PLN-SERCA interactions. Near the cytoplasmic surface of the bilayer, the PLN helix is disrupted to prevent its collision with M4. The model can be extended into the cytoplasmic domain so that Lys-3 in PLN can be cross-linked with Lys-397 and Lys-400 in SERCA1a with little unwinding of the N-terminal helix of PLN.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0237326100