Human LDL receptor (extracellular domain)
Homo sapiens (human)
It is well known that too much low-density lipoprotein (LDL) cholesterol in blood causes atherosclerosis. This condition is characterized by the formation of blood clots on the inner walls of the arteries. Already narrowed arteries are blocked. Cholesterol is produced in the liver and is needed for the synthesis of cell membranes and of certain hormones. Cholesterol bound to LDL is carried from the liver to the cells. LDL-receptor (LDL-R) located on the cell surface captures the LDL-cholesterol complex and translocates it into the cell in a process known as receptor-mediated endocytosis. Through this process LDL-R removes cholesterol-carrying lipoproteins from plasma circulation. Defective LDL-R and increased consumption of animal products high in cholesterol, such as meat, eggs and butter, inactivate LDL-R. As a result of this inactivation the level of LDL cholesterol in the blood increases, causing atherosclerosis. Because excessive cholesterol in blood and tissue is unfavorable, LDL is called bad cholesterol. High-density lipoprotein (HDL) which returns cholesterol to the liver is called good cholesterol.
LDL-R consists of two domains, the LDL-binding domain shaped like an arc and the epidermal growth factor (EGF) precursor homology domain which forms a linear array of four subgroups. After LDL bound to LDL-R is incorporated into the cell, it is enveloped by an endosome, a membrane vesicle that transports LDL in the cell. The beta-propeller, one of the four subgroups in EGF precursor homology domain, is an alternate substrate for the LDL-binding domain. In an intramolecular displacement it competes for binding with LDL, and as a result LDL-R releases LDL. The free LDL-R can then recycle to the cell surface. This process is called "lipoprotein release". This mechanism was revealed by the determination of the LDL-R structure. As described above, LDL-R regulates cholesterol homeostatis in mammalian cells through endocytosis of LDL.
Protein Data Bank (PDB)
Rudenko, G. Henry, L. Henderson, K. Ichtchenko, K. Brown, M.S. Goldstein, J.L. Deisenhofer, J.; "Structure of the LDL receptor extracellular domain at endosomal pH"; Science; (2002) 298:2353-2358 PubMed:12459547.
author: Yuko Tsuchiya