Structure of N-terminal Domain of NPC1 Reveals Distinct Subdomains for Binding and Transfer of Cholesterol

By H. Kwon, Lina Abi-Mosleh, Michael L. Wang, J. Deisenhofer, J. Goldstein, Michael S. Brown, R. Infante. 2009

666 citations recorded by the source corpus.

SUMMARY LDL delivers cholesterol to lysosomes by receptor-mediated endocytosis. Exit of cholesterol from lysosomes requires two proteins, membrane-bound Niemann-Pick C1 (NPC1) and soluble NPC2. NPC2 binds cholesterol with its isooctyl side chain buried and its 3ß-hydroxyl exposed. Here, we describe high-resolution structures of the N-terminal domain (NTD) of NPC1 and complexes with cholesterol and 25-hydroxycholesterol. NPC1(NTD) binds cholesterol in an orientation opposite to NPC2: 3ß-hydroxyl buried and isooctyl side chain exposed. Cholesterol transfer from NPC2 to NPC1(NTD) requires reorientation of a helical subdomain in NPC1(NTD), enlarging the opening for cholesterol entry. NPC1 with point mutations in this subdomain (distinct from the binding subdomain) cannot accept cholesterol from NPC2 and cannot restore cholesterol exit from lysosomes in NPC1-deficient cells. We propose a working model: after lysosomal hydrolysis of LDL-cholesteryl esters, cholesterol binds NPC2, which transfers it to NPC1(NTD), reversing its orientation and allowing insertion of its isooctyl side chain into the outer lysosomal membranes.

Subfields: Cell Biology, Physiology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

Citations in the corpus

ECOD: An Evolutionary Classification of Protein Domains (2014, background): “Together, the homologous cysteine-rich domains in Frizzled, NPC1, FRBP, and glypicans define a diverse superfamily of extracellular protein domains with an ancient eukaryotic origin and potential ligandbinding activities.”
The lysosome: from waste bag to potential therapeutic target. (2013, background): “In the predominant theory, the soluble protein NPC2 binds free cholesterol in the lysosomal lumen and transports it to NPC1 in the limiting membrane (Kwon et al., 2009).”
Structural ties between cholesterol transport and morphogen signaling. (2009, background): “These findings prompted us to make a detailed structural comparison between the cholesterol-bound N-terminal domain of human NPC1 (Kwon et al., 2009), the chicken riboflavinbinding protein docked to riboflavin (RBP; a paralog of folate receptors) (Monaco, 1997), and the FZD module of the mouse Frz8…”
Niemann-Pick disease type C (2010, background): “Based on the current stage of knowledge but fully compatible with earlier studies (reviewed in [56]) a “handoff” model has recently been proposed for the coordinated role of the two proteins [19].”