An Allosteric Binding Site on Sortilin Regulates the Trafficking of VLDL, PCSK9, and LDLR in Hepatocytes

• DOI: 10.1021/acs.biochem.0c00741
• Publication Date: 2020-11-06T03:39:00Z
• Authors: Robert P. Sparks; Andres S. Arango; Jermaine L. Jenkins; Wayne C. Guida; Emad Tajkhorshid; Charles E. Sparks; Janet D. Sparks; Rutilio A. Fratti
• Keywords: Transport protein

ApoB lipoproteins (apo B-Lp) are produced in hepatocytes, and their secretion requires the cargo receptor sortilin. We examined of apo B-Lp-containing very low-density lipoprotein (VLDL), an LDL progenitor. Sortilin also regulates trafficking subtilase PCSK9, which when secreted binds (LDLR), resulting its endocytosis destruction at lysosome. show that site 2 binding compound (cpd984) has multiple effects including (1) enhanced Apo-Lp secretion, (2) increased cellular PCSK9 retention, (3) augmented levels LDLR plasma membrane. postulate cpd984 enhances B-Lp part through lipid phosphatidylinositol 3,4,5-trisphosphate (PIP3), is present higher on circulating VLDL form fed rats relative to after fasting. attribute affinity for sortilin 1 induced by 2. This hinders would subsequently prevent leading degradation. suggests allosteric regulator binding. effect not limited VLDL, as augments neuropeptide neurotensin (NT) 1. Molecular dynamics simulations demonstrate C-terminus NT (Ct-NT) stably electrostatic interaction. was bolstered ability Ct-NT disrupt lower-affinity interactions between ligand PIP3. Together, these data allosterically regulated binding, with important ramifications homeostasis involving proteins such LDLR.