TY - JOUR
T1 - Regulation of the Ca(2+)-ATPase by cholesterol
T2 - A specific or non-specific effect?
AU - Autzen, Henriette Elisabeth
AU - Siuda, Iwona
AU - Sonntag, Yonathan
AU - Nissen, Poul
AU - Møller, Jesper Vuust
AU - Thøgersen, Lea
PY - 2015/8/11
Y1 - 2015/8/11
N2 - Like other integral membrane proteins, the activity of the Sarco/Endoplasmic Reticulum Ca(2+)-ATPase (SERCA) is regulated by the membrane environment. Cholesterol is present in the endoplasmic reticulum membrane at low levels, and it has the potential to affect SERCA activity both through direct, specific interaction with the protein or through indirect interaction through changes of the overall membrane properties. There are experimental data arguing for both modes of action for a cholesterol-mediated regulation of SERCA. In the current study, coarse-grained molecular dynamics simulations are used to address how a mixed lipid-cholesterol membrane interacts with SERCA. Candidates for direct regulatory sites with specific cholesterol binding modes are extracted from the simulations. The binding pocket for thapsigargin, a nanomolar inhibitor of SERCA, has been suggested as a cholesterol binding site. However, the thapsigargin binding pocket displayed very little cholesterol occupation in the simulations. Neither did atomistic simulations of cholesterol in the thapsigargin binding pocket support any specific interaction. The current study points to a non-specific effect of cholesterol on SERCA activity, and offers an alternative interpretation of the experimental results used to argue for a specific effect.
AB - Like other integral membrane proteins, the activity of the Sarco/Endoplasmic Reticulum Ca(2+)-ATPase (SERCA) is regulated by the membrane environment. Cholesterol is present in the endoplasmic reticulum membrane at low levels, and it has the potential to affect SERCA activity both through direct, specific interaction with the protein or through indirect interaction through changes of the overall membrane properties. There are experimental data arguing for both modes of action for a cholesterol-mediated regulation of SERCA. In the current study, coarse-grained molecular dynamics simulations are used to address how a mixed lipid-cholesterol membrane interacts with SERCA. Candidates for direct regulatory sites with specific cholesterol binding modes are extracted from the simulations. The binding pocket for thapsigargin, a nanomolar inhibitor of SERCA, has been suggested as a cholesterol binding site. However, the thapsigargin binding pocket displayed very little cholesterol occupation in the simulations. Neither did atomistic simulations of cholesterol in the thapsigargin binding pocket support any specific interaction. The current study points to a non-specific effect of cholesterol on SERCA activity, and offers an alternative interpretation of the experimental results used to argue for a specific effect.
UR - http://www-tandfonline-com.ez.statsbiblioteket.dk:2048/doi/full/10.3109/09687688.2015.1073382
U2 - 10.3109/09687688.2015.1073382
DO - 10.3109/09687688.2015.1073382
M3 - Journal article
C2 - 26260074
SN - 0968-7688
VL - 32
SP - 75
EP - 87
JO - Molecular Membrane Biology
JF - Molecular Membrane Biology
IS - 3
ER -