Aggregation of β2-Glycoprotein I Induced by Sodium Lauryl Sulfate and Lysophospholipids

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Abstract
β2-Glycoprotein I (β2-GPI) is a plasma protein that binds to negatively charged substances such as DNA, heparin, and anionic phospholipids. The interaction of β2-GPI with anionic phospholipids is intriguing in the context of the autoimmune disease antiphospholipid syndrome. To extend understanding of the binding mechanism to phospholipids, the interactions of β2-GPI with amphiphiles, i.e., sodium lauryl sulfate and lysophospholipids, were examined. These amphiphiles induced the aggregation of β2-GPI below the critical micelle concentration, indicating that the interaction of β2-GPI with monodispersed amphiphiles is unstable, resulting in the formation of large aggregates. However, highly soluble monocaproylphosphatidic acid did not induce aggregation, suggesting that the hydrophobicity of the acyl chain is also an important factor for aggregate formation in addition to negative charges in the headgroup. A series of experiments using deletion mutants and a peptide showed that the fifth domain of β2-GPI (domain V) is responsible for formation of aggregates observed for intact full-length β2-GPI. In addition, the flexible loop (F307−C326) in the C-terminal of domain V, which consists of hydrophobic and positively charged residues, was identified as the important region for aggregation. These results indicate that β2-GPI binds to the amphiphiles through the flexible loop of domain V, resulting in formation of large aggregates where both electrostatic and hydrophobic interactions are involved.

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