4.7 Article

Structure-function analysis of naturally occurring apolipoprotein A-I L144R, A164S and L178P mutants provides insight on their role on HDL levels and cardiovascular risk

期刊

CELLULAR AND MOLECULAR LIFE SCIENCES
卷 78, 期 4, 页码 1523-1544

出版社

SPRINGER BASEL AG
DOI: 10.1007/s00018-020-03583-y

关键词

Apolipoprotein A-I; High-density lipoprotein; Mutant; Protein conformation; ApoA-I; HDL functional properties; Coronary artery disease

资金

  1. European Union (European Regional Development Fund)
  2. Leducq Foundation for Cardiovascular Research
  3. An Open-Access Research Infrastructure of Chemical Biology and Target-Based Screening Technologies for Human and Animal Health, Agriculture and the Environment (OPENSCREEN-GR) - Operational Programme Competitiveness, Entrepreneurship and Innovation (NSRF [MIS 5002691]
  4. The National Research Infrastructure on Integrated Structural Biology, Drug Screening Efforts and Drug target functional characterization (INSPIRED) - Operational Programme Competitiveness, Entrepreneurship and Innovation (NSRF 2014-2020) [MIS 5002550]
  5. A Greek Research Infrastructure for Visualizing and Monitoring Fundamental Biological Processes (BioImaging-GR) - Operational Programme Competitiveness, Entrepreneurship and Innovation (NSRF 2014-2020) [MIS 5002755]

向作者/读者索取更多资源

Our study showed that mutations in apoA-I can lead to structural and thermodynamic aberrations, as well as functional defects that impair cholesterol efflux capacity and endothelial cell functions. Mutants in reconstituted HDL were more thermodynamically destabilized and exhibited reduced cholesterol efflux capacity, as well as defects in promoting endothelial cell migration and Akt kinase activation. These findings provide insights into how these mutations affect HDL-cholesterol levels and cardiovascular risk.
Naturally occurring point mutations in apolipoprotein A-I (apoA-I), the major protein component of high-density lipoprotein (HDL), may affect plasma HDL-cholesterol levels and cardiovascular risk. Here, we evaluated the effect of human apoA-I mutations L144R (associated with low HDL-cholesterol), L178P (associated with low HDL-cholesterol and increased cardiovascular risk) and A164S (associated with increased cardiovascular risk and mortality without low HDL-cholesterol) on the structural integrity and functions of lipid-free and lipoprotein-associated apoA-I in an effort to explain the phenotypes of subjects carrying these mutations. All three mutants, in lipid-free form, presented structural and thermodynamic aberrations, with apoA-I[L178P] presenting the greatest thermodynamic destabilization. Additionally, apoA-I[L178P] displayed reduced ABCA1-mediated cholesterol efflux capacity. When in reconstituted HDL (rHDL), apoA-I[L144R] and apoA-I[L178P] were more thermodynamically destabilized compared to wild-type apoA-I, both displayed reduced SR-BI-mediated cholesterol efflux capacity and apoA-I[L144R] showed severe LCAT activation defect. ApoA-I[A164S] was thermodynamically unaffected when in rHDL, but exhibited a series of functional defects. Specifically, it had reduced ABCG1-mediated cholesterol and 7-ketocholesterol efflux capacity, failed to reduce ROS formation in endothelial cells and had reduced capacity to induce endothelial cell migration. Mechanistically, the latter was due to decreased capacity of rHDL-apoA-I[A164S] to activate Akt kinase possibly by interacting with endothelial LOX-1 receptor. The impaired capacity of rHDL-apoA-I[A164S] to preserve endothelial function may be related to the increased cardiovascular risk for this mutation. Overall, our structure-function analysis of L144R, A164S and L178P apoA-I mutants provides insights on how HDL-cholesterol levels and/or atheroprotective properties of apoA-I/HDL are impaired in carriers of these mutations.

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