%0 Online Multimedia
%A Mouchlis, Varnavas D.
%A Chen, Yuan
%A McCammon, J. Andrew
%A Dennis, Edward A.
%D 2018
%T Membrane
Allostery and Unique Hydrophobic Sites Promote
Enzyme Substrate Specificity
%U https://acs.figshare.com/articles/media/Membrane_Allostery_and_Unique_Hydrophobic_Sites_Promote_Enzyme_Substrate_Specificity/5926165
%R 10.1021/jacs.7b12045.s012
%2 https://acs.figshare.com/ndownloader/files/10592593
%K specificity
%K Unique Hydrophobic Sites Promote Enzyme Substrate Specificity
%K surface binding moieties
%K phospholipase
%K headgroup binding site
%K enzyme
%K proinflammatory arachidonic acid
%K linoleic acid
%K Molecular dynamics simulations
%K membrane phospholipid substrates
%K phospholipid binding mode
%X We
demonstrate that lipidomics coupled with molecular dynamics
reveal unique phospholipase A2 specificity toward membrane
phospholipid substrates. We discovered unexpected headgroup and acyl-chain
specificity for three major human phospholipases A2. The
differences between each enzyme’s specificity, coupled with
molecular dynamics-based structural and binding studies, revealed
unique binding sites and interfacial surface binding moieties for
each enzyme that explain the observed specificity at a hitherto inaccessible
structural level. Surprisingly, we discovered that a unique hydrophobic
binding site for the cleaved fatty acid dominates each enzyme’s
specificity rather than its catalytic residues and polar headgroup
binding site. Molecular dynamics simulations revealed the optimal
phospholipid binding mode leading to a detailed understanding of the
preference of cytosolic phospholipase A2 for cleavage of
proinflammatory arachidonic acid, calcium-independent phospholipase
A2, which is involved in membrane remodeling for cleavage
of linoleic acid and for antibacterial secreted phospholipase A2 favoring linoleic acid, saturated fatty acids, and phosphatidylglycerol.
%I ACS Publications