Apolipoprotein-A1 transports and regulates MMP2 in the blood

Abstract

Abstract Synthesized in the liver and intestines, apolipoprotein A1 (ApoA1) is the major protein component of high-density lipoprotein (HDL) particles and transports cholesterol from peripheral organs to the liver. This interorgan communication strategy may protect against atherogenesis by sequestering cholesterol from atherosclerotic lesions. Here, we found that ApoA1 has high affinity for the catalytic groove and fibronectin-like repeats of matrix metalloproteinase 2 (MMP2), the most abundant MMP in human blood. In healthy humans and ApoA1-expressing mice, we found that MMP2 is associated with ApoA1 in HDL. We confirmed the ApoA1/MMP2 interactions using five orthogonal interaction proteomics assays. Strikingly, we found that Apoa1 can allosterically increase the proteolytic activity of MMP2—an effect not observed in ApoA1-deficient plasma from ApoA1 KO mice. This finding was not predictable, as MMP2 was not previously known to be an allosteric enzyme. Using a high-confidence artificial intelligence (AlfaFold)-based structural model of the ApoA1/MMP2 complex, we explain how ApoA1 binds and allosterically regulates MMP2. We suggest that ApoA1 sequesters MMP2 in the blood circulation and redistributes it to ApoA1 target organs, such as the liver. This interorgan communication mechanism is independent of canonical reverse cholesterol transport by ApoA1/HDL and may prevent MMP2-mediated rupture of atherosclerotic plaques. Graphical Abstract