In this article, the history of the LDL receptor is recounted by its codiscoverers. Their early work on the LDL receptor explained a genetic cause of heart attacks and led to new ways of thinking about cholesterol metabolism. The LDL receptor discovery also introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. The latter concept provides the mechanism by which statins selectively lower plasma LDL, reducing heart attacks and prolonging life.

The LDL Receptor

Niemann-Pick disease type C (NPC) is an autosomal recessive neurovisceral lipid storage with a wide spectrum of clinical phenotypes. At the cellular level, the disorder is characterized by accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system. Approximatively 95% of patients have mutations in the NPC1 gene (mapped at 18q11) which encodes a large membrane glycoprotein primarily located to late endosomes. The remainder have mutations in the NPC2 gene (mapped at 14q24.3) which encodes a small soluble lysosomal protein with cholesterol-binding properties. The identical biochemical patterns observed in NPC1 and NPC2 mutants suggest that the two proteins function in a coordinate fashion. Identification of mutations revealed a complex picture of molecular heterogeneity, allowing genotype - phenotype correlations for both genes and providing insights into structure - function relationships for the NPC1 protein. Although a whole body of evidence suggests that the NPC1 and NPC2 proteins are involved in the cellular postlysosomal/late endosomal transport of cholesterol, glycolipids and other cargo, their precise functions and relationship remain unclear and are currently the subject of intense investigation. These studies, conducted in various models, should ultimately lead to a better understanding of the pathophysiology of NPC and new therapeutic approaches.

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Niemann-Pick disease type C.

Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol.

The steroidogenic acute regulatory protein (StAR) regulates acute steroidogenesis in the adrenal cortex and gonads by promoting the translocation of cholesterol to the mitochondrial inner membrane where the first step in steriod biosynthesis is catalyzed. StAR-related lipid transfer (START) domains occur in proteins involved in lipid transport and metabolism, signal transduction, and transcriptional regulation. The 2.2 A resolution crystal structure of the START domain of human MLN64 reported here reveals an alpha/beta fold built around a U-shaped incomplete beta-barrel. The interior of the protein encompasses a 26 x 12 x 11 A hydrophobic tunnel that is large enough to bind a single cholesterol molecule. The StAR and MLN64 START domains bind 1 mole of 14C cholesterol per mole of protein in vitro. Based on the START domain structure and cholesterol binding stoichiometry, it is proposed that StAR acts by shuttling cholesterol molecules one at a time through the intermembrane space of the mitochondrion.

Structure and lipid transport mechanism of a StAR-related domain.

Sphingolipids and glycosphingolipids are membrane components of eukaryotic cell surfaces. Their constitutive degradation takes place on the surface of intra-endosomal and intra-lysosomal membrane structures. During endocytosis, these intra-lysosomal membranes are formed and prepared for digestion by a lipid-sorting process during which their cholesterol content decreases and the concentration of the negatively charged bis(monoacylglycero)phosphate (BMP)--erroneously also called lysobisphosphatidic acid (LBPA)--increases. Glycosphingolipid degradation requires the presence of water-soluble acid exohydrolases, sphingolipid activator proteins, and anionic phospholipids like BMP. The lysosomal degradation of sphingolipids with short hydrophilic head groups requires the presence of sphingolipid activator proteins (SAPs). These are the saposins (Saps) and the GM2 activator protein. Sphingolipid activator proteins are membrane-perturbing and lipid-binding proteins with different specificities for the bound lipid and the activated enzyme-catalyzed reaction. Their inherited deficiency leads to sphingolipid- and membrane-storage diseases. Sphingolipid activator proteins not only facilitate glycolipid digestion but also act as glycolipid transfer proteins facilitating the association of lipid antigens with immunoreceptors of the CD1 family.

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Takayuki Kashima

Papers

A porcine homolog of the major secretory protein of human epididymis, HE1, specifically binds cholesterol.