Niemann-Pick C2 (NPC2) and intracellular cholesterol trafficking

Abstract

Cholesterol is an important precursor for numerous biologically active molecules, and it plays a major role in membrane structure and function. Cholesterol can be endogenously synthesized or exogenously taken up via the endocytic vesicle system and subsequently delivered to post-endo/lysosomal sites including the plasma membrane and the endoplasmic reticulum. Niemann-Pick C (NPC) disease results in the accumulation of exogenously-derived cholesterol, as well as other lipids, in late endosomes and lysosomes (LE/LY). Identification of the two genes that underlie NPC disease, NPC1 and NPC2, has focused attention on the mechanisms by which lipids, in particular cholesterol, are transported out of the LE/LY compartment. This review discusses the role of the NPC2 protein in cholesterol transport, and the potential for concerted action of NPC1 and NPC2 in regulating normal intracellular cholesterol homeostasis.

Fig. 1

Crystal structure of bovine NPC2 (bNPC2)-cholesterol sulfate complex (PDB ID: 2HKA). Structures generated with Accelrys DS Visualizer (www.accelrys.com). (A) Solid ribbon style, colored by secondary structure type. R32, D72 and K75 are highlighted; these residues in bNPC2 are identical or homologous to those identified in murine NPC2 as being able to bind cholesterol normally, but as unable to clear the cholesterol accumulation in NPC2-deficient cells [61]. (B) Solvent surface style, with probe radius of 1.4 Å, colored by electrostatic potential – red indicates positively charged, blue indicates negatively charged, and white indicates neutral residues.

Fig. 2

Alignment of mammalian NPC2 sequences. The 19 amino acid signal sequences are shown. NPC2 sequences are numbered starting with the first amino acid after the signal peptide, marked with an arrow. Residues with hydrophobic side chains are colored in red, and residues with hydrophilic side chains are colored in blue (acidic), magenta (basic) and green (neutral). * indicates identical residues, : indicates conserved residues, and . indicates semi-conserved residues.

Fig. 3

Potential role of NPC2 in the egress of cholesterol from the late endosomal/ lysosomal compartment. CE, cholesteryl ester; FA, unesterified fatty acid; LBPA/BMP, lyso-bis phosphatidic acid, also known as bis(monoacylglycerol)phosphate.