Structural basis of specific interactions of Lp-PLA2 with HDL revealed by hydrogen deuterium exchange mass spectrometry.

Abstract

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), specifically Group VIIA PLA(2), is a member of the phospholipase A(2) superfamily and is found mainly associated with LDL and HDL in human plasma. Lp-PLA(2) is considered as a risk factor, a potential biomarker, a target for therapy in the treatment of cardiovascular disease, and evidence suggests that the level of Lp-PLA(2) in plasma is associated with the risk of future cardiovascular and stroke events. The differential location of the enzyme in LDL/HDL lipoproteins has been suggested to affect Lp-PLA(2) function and/or its physiological role and an abnormal distribution of the enzyme may correlate with diseases. Although a mutagenesis study suggested that a surface helix (residues 362-369) mediates the association between Lp-PLA(2) and HDL, the molecular details and mechanism of association has remained unknown. We have now employed hydrogen deuterium exchange mass spectrometry to characterize the interaction between recombinant human Lp-PLA(2) and human HDL. We have found that specific residues 113-120, 192-204, and 360-368 likely mediate HDL binding. In a previous study, we showed that residues 113-120 are important for Lp-PLA(2)-liposome interactions. We now find that residues 192-204 show a decreased deuteration level when Lp-PLA(2) is exposed to apoA-I, but not apoA-II, the most abundant apoproteins in HDL, and additionally, residues 360-368 are only affected by HDL.The results suggest that apoA-I and phospholipid membranes play crucial roles in Lp-PLA(2) localization to HDL.

• Authors: Jian Cao, Yuan-Hao Hsu, Sheng Li, Virgil L Woods Jr, Edward A Dennis
• Journal: Journal of lipid research (J Lipid Res) Vol. 54 Issue 1 Pg. 127-33 (Jan 2013) ISSN: 1539-7262 [Electronic] United States
• PMID: 23089916 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Apolipoprotein A-I
• Lipoproteins, HDL
• 1-Alkyl-2-acetylglycerophosphocholine Esterase

Topics

• 1-Alkyl-2-acetylglycerophosphocholine Esterase (chemistry, metabolism)
• Apolipoprotein A-I (chemistry, metabolism)
• Binding Sites
• Deuterium Exchange Measurement
• Humans
• Lipoproteins, HDL (metabolism)
• Mass Spectrometry
• Models, Molecular
• Protein Binding
• Protein Conformation