Fig. 8

Schematic diagram showing the predicted 3D structure of FACI and its role on clathrin-mediated LDLR endocytosis. A Predicted 3D structure of FACI by AlphaFold2 [59]. FACI protein is composed of two parts: N-terminal intrinsic disorder region (IDR) and C-terminal helix region. C-terminal helix region consists of Motifs D (DxxxLI) and E (PIP2-binding motif). N-terminal IDR contains Motifs A (RxxpS), B (YxxL) and C (RxxpS). Motifs A and C are two phosphorylated motifs with unknown function, which are conserved among mammalian FACI homologs. pLDDT: per-residue confidence score. Regions below 50 pLDDT may be unstructured in isolation. B The role of FACI in clathrin-mediated LDLR endocytosis. FACI is an integral monotopic protein or a peripheral membrane protein. Its C-terminal amphipathic α-helix-containing motif (Motif E) mediates the binding with membrane phosphatidylinositol, while the N-terminal IDR is “string-like” in the cytoplasm. Under some conditions, FACI is recruited by membrane PIP2. PIP2-bound FACI further recruits the AP2 complex by its DxxxLI motif (Motif D), which drives or promotes assembly of CCVs. FACI increases the efficiency of LDLR endocytosis, which attenuates diet-induced hypercholesterolemia in mice