NPC intracellular cholesterol transporter 1 (NPC1)-mediated cholesterol export from lysosomes

Abstract

Low-density lipoprotein particles are taken up by cells and delivered to the lysosome where their cholesterol esters are cleaved off by acid lipase. The released, free cholesterol is then exported from lysosomes for cellular needs or storage. This article summarizes recent advances in our understanding of the molecular basis of cholesterol export from lysosomes. Cholesterol export requires NPC intracellular cholesterol transporter 1 (NPC1) and NPC2, genetic mutations of which can cause Niemann-Pick type C disease, a disorder characterized by massive lysosomal accumulation of cholesterol and glycosphingolipids. Analysis of the NPC1 and NPC2 structures and biochemical properties, together with new structures of the related Patched (PTCH) protein, provides new clues to the mechanisms by which NPC proteins may function.

Keywords: Hedgehog; NPC intracellular cholesterol transporter; NPC1; NPC2; Niemann-Pick C disease; Patched; cholesterol; cholesterol transport; cholesterol-binding protein; low-density lipoprotein (LDL); lysosome; lysosomes; sterol metabolism; transporter.

Figure 1.

Structures of NPC1, NPC2 and PTCH proteins. A, NPC1 bound to NPC2 (24). Lumenal domains 1, 2, and 3 are shown in red, blue, and yellow, respectively; NPC2 with bound cholesterol is shown in green. B, NPC1 structure (22) onto which peptides (red) are mapped that could be crosslinked to a clickable, photocrosslinker (32). Note that the entire peptide is shown, rather than the precise site of crosslinking. C, PTCH structure with bound, palmitoylated Sonic hedgehog (red) (29). Note the palmitoyl moiety that reaches deep into the core of the protein.

Figure 2.

Structures of cholesterol and related molecules discussed herein. Numbers refer to the adjacent carbon atom. Orange dashed circles highlight major differences compared with cholesterol.