@article {26548,
	title = {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},
	journal = {Cell Mol Life SciCell Mol Life SciCell Mol Life Sci},
	volume = {78},
	number = {4},
	year = {2021},
	note = {Gkolfinopoulou, ChristinaSoukou, FayeDafnis, IoannisKellici, Tahsin FSanoudou, DespinaMavromoustakos, ThomasStratikos, EfstratiosChroni, AngelikiengMIS 5002691/Operational Programme "Competitiveness, Entrepreneurship and Innovation" (NSRF 2014-2020)MIS 5002550/Operational Programme "Competitiveness, Entrepreneurship and Innovation" (NSRF 2014-2020)MIS 5002755/Operational Programme "Competitiveness, Entrepreneurship and Innovation"Switzerland2020/07/16 06:00Cell Mol Life Sci. 2021 Feb;78(4):1523-1544. doi: 10.1007/s00018-020-03583-y. Epub 2020 Jul 14.},
	month = {Feb},
	pages = {1523-1544},
	abstract = {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.},
	keywords = {Apolipoprotein A-I/*genetics/metabolism/ultrastructure, ATP Binding Cassette Transporter, Subfamily G, Member 1/*genetics/metabolism, Cardiovascular Diseases/*genetics/pathology, Cell Movement/genetics, Cholesterol, HDL/*genetics/metabolism/ultrastructure, Endothelial Cells/metabolism/pathology, Heart Disease Risk Factors, Humans, Ketocholesterols/genetics/metabolism, Lipoproteins, HDL/genetics/metabolism/ultrastructure, Mutant Proteins/genetics/metabolism/ultrastructure, Mutation/genetics, Scavenger Receptors, Class E/genetics/metabolism, Structure-Activity Relationship, thermodynamics},
	isbn = {1420-9071 (Electronic)1420-682X (Linking)},
	author = {Gkolfinopoulou, C. and Soukou, F. and Dafnis, I. and Kellici, T.F. and Sanoudou, D. and Mavromoustakos, T. and Stratikos,E. and Chroni, A.}
}
