Heparin-derived oligosaccharides interact with the phospholamban cytoplasmic domain and stimulate SERCA function.
The association between the cardiac transmembrane proteins phospholamban and sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) regulates the active transport of Ca(2+) into the sarcoplasmic reticulum (SR) lumen and controls the contraction and relaxation of the heart. Heart failure (HF) and cardiac hypertrophy have been linked to defects in Ca(2+) uptake by the cardiac SR and stimulation of calcium transport by modulation of the PLB-SERCA interaction is a potential therapy. This work is part of an effort to identify compounds that destabilise the PLB-SERCA interaction in well-defined membrane environments. It is shown that heparin-derived oligosaccharides (HDOs) interact with the cytoplasmic domain of PLB and consequently stimulate SERCA activity. These results indicate that the cytoplasmic domain of PLB is functionally important and could be a valid target for compounds with drug-like properties.
Hughes
Eleri
E
School of Biological Sciences, University of Liverpool, Crown Street, Liverpool L69 7ZB, United Kingdom.
Edwards
Rachel
R
Middleton
David A
DA
D000818:Animals; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology*; D009844:Oligosaccharides / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary / Q000187:drug effects; D011817:Rabbits; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D006493:Heparin; D009844:Oligosaccharides; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban