Structure‐based mechanism for the adaptation of apolipoprotein A‐I to the changing lipid load in Good Cholesterol

Abstract

High‐density lipoproteins (HDL) and their main protein, apoA‐I, remove excess cell cholesterol and protect against atherosclerosis. Heterogeneity and large size of HDL (8–12 nm) hamper their high‐resolution structural studies. Low‐resolution studies showed that two apoA‐I molecules form an antiparallel α‐helical double belt around an HDL particle. High‐resolution structure of the C‐terminally truncated apoA‐I solved by Mei and Atkinson provides tremendous new insights into HDL structure‐function. It enables us to propose apoA‐I conformations on the small, midsize and large HDL and validate them by comparison with extensive biophysical data. We postulate that the central “constant” half of the double belt is structurally conserved while the N‐and C‐terminal “variable” half re‐arranges upon HDL growth. This includes sequential unhinging of the N‐terminal bundle around two flexible Gly‐containing regions to elongate the belt, along with concerted swing motion of the double belt around G65‐P66 and G185‐G186 hinges that are aligned on various‐size particles, to confer 2D surface curvature to spherical HDL. Our ensemble reconciles several existing HDL models and helps provide a structural framework for understanding functional interactions with ~60 other HDL‐associated proteins and, ultimately, to improve cardioprotective function of HDL. This work was supported by NIH grants HL026355 and GM067260.