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Interaction of LDL receptor family members with ligands

Institution: Children's Hospital Oakland Research Institute
Investigator(s): Taichi Yamamoto, Ph.D.
Award Cycle: 2008 (Cycle 17) Grant #: 17KT-0026 Award: $266,162
Subject Area: Cardiovascular Disease
Award Type: New Investigator Awards
Abstracts

Initial Award Abstract
Considerable previous research has shown that exposure to secondhand tobacco smoke increases the risk of cardiovascular disease. Not only tobacco smokers, but also persons exposed to secondhand tobacco smoke are susceptible to vascular injury and atherosclerosis lesion development. Although there is much scientific and epidemiological evidence that demonstrates the relationship between tobacco smoke exposure and cardiovascular disease, we are only beginning to understand how smoking contributes to the onset and progression of cardiovascular disease at the molecular level. Understanding the molecular mechanisms involved in the relationship between tobacco smoke and cardiovascular disease will be useful for the design of new therapeutic strategies to prevent or treat tobacco related disease.

Cholesterol is incorporated with protein into transport packages that travel in the blood, termed lipoproteins. Low-density lipoprotein (LDL) is known as a “bad cholesterol” since it seems to accumulate in blood vessel walls, plugging them. Circulating LDL is a spherical particle containing ~1500 molecules of cholesterol attached to fatty acids and surrounded by an envelope of phospholipids. LDL receptor (LDLR) recognizes LDL on the surface of cells and functions in removal of lipoproteins from the bloodstream. Any deficiency or defects of LDLR will reduce the efficiency of LDL removal from the bloodstream. A genetic disorder of LDLR, familial hypercholesterolemia, accelerates atherosclerosis and leads to cardiovascular disease. LDLR interacts with accessory proteins that regulate its function. Apolipoprotein E (apoE) is recognized by LDLR and is widely distributed among lipoprotein particles. The interaction between LDLR and apoE plays a critical role in removal of lipoprotein particles from the bloodstream. These lipoprotein particles are targets for tobacco smoke-related oxidative damage. An oxidized particle, such as those generated upon exposure to cigarette smoke, accelerates the progression of atherosclerosis lesion development. Therefore, understanding the molecular mechanism of the interaction between LDLR and apoE will contribute to development of therapeutic strategies to prevent or treat cardiovascular disease. We will study the binding interaction between LDLR and apoE.

In addition, a relatively new accessory protein, proprotein convertase subtilisin kexin 9 (PCSK9), has been identified. PCSK9 has been shown to inhibit the function of LDLR by inducing LDLR protein degradation. Inhibition of PCSK9 function may result in greater numbers of active LDLR at the cell surface. In fact, there is scientific evidence from animal experiments that inhibition of PCSK9 results in resistance against high plasma cholesterol. In proposed research the binding interaction between LDLR and PCSK9 will be studied.

LDL receptor-related protein (LRP) 5 and LRP6 are LDLR family members that also play critical roles in lipid metabolism. In 2007, human subject studies showed that a single missense mutation in LRP6 was strongly correlated with hyperlipidemia and premature atherosclerosis. While LRP5 is known to recognize apoE as a ligand and to function in regulation of normal lipid metabolism, the molecular mechanism behind LRP6 function in cholesterol homeostasis is unknown. We hypothesize that apoE will function as a ligand for LRP6. Further, it is postulated that the mutant LRP6 associated with premature cardiovascular disease in humans, will be defective in apoE binding.

Our studies are designed to ascertain the interaction between LDLR members and ligand/accessory proteins, and to evaluate the role of specific architectural features as modulators of cholesterol homeostasis and lipid metabolism. These studies will increase our knowledge of molecular aspects of LDLR family members and ligand/accessory proteins in regulating lipoprotein levels in plasma, and provide the basis for new strategies to decrease tobacco smoke-exposure related lipoprotein damage that promotes and accelerates the pathology of cardiovascular disease.
Publications

Protein engineering reveals LDL type A repeat order affects ligand binding to the in low-density lipoprotein receptorl
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Yamamoto, T; Ryan, RO ART
Yr: 2009 Vol: 284 Nbr: Abs: Pg: 13396-13400

Semisythesis and segmental isotope labeling of apoE3 N-terminal domain using expressed protein ligation.
Periodical: Journal of Lipid Research Index Medicus:
Authors: Hauser PS, Raussens V, Yamamoto T, Abdullahi GE, Weers PM, Sykes BD, Ryan RO, ART
Yr: 2009 Vol: 50 Nbr: Abs: Pg: 1548 - 1555