Structure of human Niemann‐Pick C1 (NPC1) protein and NPC1‐NPC2 complex

Cholesterol, essential for all animal life, plays a vital role for maintenance of membrane strength and permeability, also serves as a precursor for the biosynthesis of lipoprotein, steroid hormones, bile acid and vitamin D. Our major cholesterol sources are endogenous biosynthesis and diet uptake. Egress of LDL‐derived cholesterol from lysosomes requires two lysosomal proteins, integral membrane protein NPC1 and soluble NPC2. Mutations on NPC1 and NPC2 can cause the inborn errors Niemann‐Pick disease, type C, which lead to the early death of the patients; remarkably. We reported the structure of NPC1 at 3.3Å resolution, which reveals internal two‐fold pseudo symmetry along TMs 2–13, and two structurally homologous domains that protrude 60Å into the lysosomal lumen. The sterol‐sensing domain (SSD) of NPC1 presents an outward‐open conformation and has a very cavity, which might transport/sense the cholesterol through the limiting membrane. Two luminal domains [Middle lumenal Domain (MLD) and C‐terminal Domain (CTD)] shared the similar fold. We also determined the 2.4Å resolution crystal structure of a complex of human NPC1‐MLD and NPC2 bearing bound cholesterol‐3‐O‐sulfate. NPC1‐MLD utilizes two protruding loops to bind NPC2, analogous to its interaction with the primed Ebola virus glycoprotein. These works present the atomic resolution models for cholesterol biogenesis and trafficking, provide the molecular insights into cholesterol transfer in lysosomal lumen and pathogenesis of Niemann‐Pick disease, type C. Support or Funding Information Life Sciences Research Foundation