MYLIP/IDOL is a regulator of the LDL receptor (LDLR) pathway via the nuclear receptor liver X receptor (LXR). In response to cellular cholesterol loading, the activation of LXR leads to the induction of MYLIP expression. MYLIP stimulates ubiquitination of the LDLR on its cytoplasmic tail, directing its degradation. The LXR-MYLIP-LDLR pathway provides a complementary pathway to sterol regulatory element-binding proteins for the feedback inhibition of cholesterol uptake. MYLIP has an N-terminal FERM domain and in some cases a C-terminal RING domain [, ].The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. Like most other ERM members they have a phosphoinositide-binding site in their FERM domain. The FERM C domain is the third structural domain within the FERM domain. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs) , the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites [, ].
This entry includes a group of ER-resident saposin-like proteins, including CNPY1/2 from mammals and protein seele from Drosophila melanogaster. They contain a saposin B-type domain, which is an endoplasmic reticulum (ER) retention domain. Seele is involved in embryonic dorsal-ventral patterning []. Zebrafish CNPY1 acts as a positive feedback regulator of FGF that contributes to the development of left-right body asymmetry by controlling stem cell clustering during Kupffer's vesicle organogenesis []. CNPY2 interacts with MYLIP, an E3 ubiquitin ligase that marks its targets for lysosomal degradation. CNPY2 protects targets of MYLIP from lysosomal degradation [].
