Johann Deisenhofer (2014) - Structural Studies on Cholesterol Transport

Johann Deisenhofer (2014)

Structural Studies on Cholesterol Transport

Johann Deisenhofer (2014)

Structural Studies on Cholesterol Transport

Abstract

Cholesterol has two essential functions in our bodies: It is an important component of cell membranes and it serves as the starting material for the synthesis of bile acids, steroid hormones, and other compounds. The human body obtains necessary cholesterol by intracellular synthesis and by dietary uptake. Cholesterol is packaged in the liver and transported in the bloodstream primarily in the form of low density lipoprotein (LDL), a complex of phospholipids, cholesterol, cholesteryl esters, and apolipoprotein B.

The LDL receptor, a membrane anchored protein of 839 amino acids, mediates the uptake of LDL into the cellular interior. This receptor binds LDL at neutral pH with high affinity, and releases it when the pH drops below ~6, as happens in endosomes during endocytosis. A crystallographic study of the extracellular portion of the receptor (amino acids 1-699) in its low-pH form shows the protein in a conformation that disables binding of LDL.

The protein PCSK9 (Proprotein Convertase Subtilisin Kexin 9), discovered in 2003, lowers the efficiency of the LDL uptake system by accelerating the degradation of LDL receptors. PCSK9 has therefore become a target for newly developed drugs that can disrupt its interaction with the receptor and thus complement the statins in lowering the blood LDL level.

In my talk I will describe structures of LDL and the LDL receptor, as well as details of the
interaction between PCSK9 and the LDL receptor.

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