Interpretation:
Using the active model for Niemann-Pick C1, the structure of the sterol-binding pocket, and the interaction involved in cholesterol binding should be described.
Concept Introduction:
Niemann-Pick C1 protein (NPC1) is a endosomal membrane protein required for transport of LDL derived cholesterol into cells. NPC1 consists with a sterol sensing domain (SSD) which is similar to SSDs in protein responsible for cholesterol biosynthesis, uptake and signaling. NPC1’s SSD forms a cavity that is accessible from both luminal bilayer leaflet and the endosomal lumen. According to the computational modeling, it is suggested that this cavity is large enough to be occupied by one cholesterol molecule.
Cholesterol is transported as cholesterol esters which are packed in lipoproteins such as low density lipoproteins (LDL). LDL is transported to endosomes and lysosomes and they are subjected to lipolysis by lipase. Then released cholesterol is bound one molecule at a time to soluble intraliposomal protein, Niemann-Pick C2 (NPC2). NCP2 bound cholesterol is then transferred to another pocket in N-terminal domain of NPC1. Here the cholesterol is bound in opposite orientation. N terminal domain of NPC1 is connected via a proline rich region to transmembrane segment 1 (TM1).
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Chapter 24 Solutions
Biochemistry
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