Recent Research Developments

Structure and Membrane Interactions of Phospholamban

Phospholamban and sarcolipin are integral membrane protein that regulates the contractility of cardiac muscle by maintaining cardiomyocyte calcium homeostasis.  Abnormalites in association of protein kinase A with phospholamban have recently been linked to human heart failure, where a single mutation is responsible for dilated cardiomyopathy (see Figure 1).  To date, a high-resolution structure of phospholamban in a lipid environment has been elusive.  Jamillah Zamoon and Alessandro Mascioni in Veglia’s laboratory have determined the first structure of recombinant, monomeric, biologically active phospholamban in lipid-mimicking dodecylphosphocholine micelles using multidimensional NMR experiments (Zamoon et al. Biophys. J. Oct. issue, 85, 2003).  The overall structure of phospholamban is "L-shaped" with the hydrophobic domain approximately perpendicular to the cytoplasmic portion. This is in agreement with our previously published solid-state NMR data (Mascioni et al. >J Am Chem Soc 124, 9392, 2002).  In addition, there are two striking discrepancies between our structure and those reported previously for synthetic phospholamban in organic solvents:  a) in our structure, the orientation of the cytoplasmic helix is consistent with the amphipathic nature of these residues, and b) within the hydrophobic helix, residues are positioned on two discrete faces of the helix as consistent with their functional roles ascribed by mutagenesis.  This topology renders the two phosphorylation sites, Ser 16 and Thr 17, more accessible to kinases (Figure 2).

Taken with the high-resolution structure of sarcolipin that Veglia’s group has recently elucidated (Mascioni et al. Biochemistry 41, 475, 2002), the determination of the phospholamban’s structure and topology represents another important step to understand cardiac muscle function and malfunctions.

Figure 1: normal heart (center), hypertrophic (left) and dilated (right) cardiomypoathies. Adapted from Marx Science 2003.

Figure 2: High-resolution structure of phospholamban lipids (Zamoon et al. Biophys J Oct. issue 85, 2003)

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