User:Giselle Flores/Sandbox 1
From Proteopedia
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| - | =Lipoprotein Lipase | + | =Lipoprotein Lipase coupled with GPIHBP1= |
<StructureSection load='6ob0' size='350' side='right' caption='Lipoprotein Lipase PDB' scene='87/877513/Original_scene/1'> | <StructureSection load='6ob0' size='350' side='right' caption='Lipoprotein Lipase PDB' scene='87/877513/Original_scene/1'> | ||
Revision as of 21:31, 27 April 2021
Lipoprotein Lipase coupled with GPIHBP1
Introduction(LPL) is an important enzyme for the breakdown of triglycerides in the body (Figure 1). Structural OverviewLPLis assumed to only be active as a , however, previous studies have argued that the lipase can be active in its . (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442593/) The N-terminal domain of lipoprotein lipase is known to consist of an alpha/beta hydrolase domain, which is composed of six alpha helices and ten beta-strands. This domain creates an . The C-terminal domain of lipoprotein lipase is composed of twelve beta strands which form a "". GPIHBP1Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) is a secondary domain that is critical to the stabilization, function, and movement of . The GPIHBP1’s highly acidic and intrinsically disordered N-terminal domain are essential to the binding of LPL’s C-terminal Domain. It has been shown that GPIHBP1 has three “finger” domains, which hold it tightly to LPL by . The importance of GPIBP1’s affinity to LPL was analyzed by Birrane et al.[1], and it was found that missense mutations of critical residues resulted in high amounts of impairments . It was also concluded that these impairments caused different profound diseases. Structural HighlightsCalcium Ion StabilizationIons are widely used in proteins and mechanismistic stabilization in many areas of biochemistry. LPL’s tertiary folding is stabilized by a Calcium (Ca2+) ion. The calcium ion shares electron density with surrounding residues in order to orient the protein in its formal state. The is achieved by the calcium ion’s interactions with the following of LPL’s residues: Ala194, Arg197, Ser199, Asp201, and Asp202. Lid and Lipid Binding RegionIn the presence of the GPIHBP1 inhibitor, the and lipid binding region become visible within the structure. As displayed through a study conducted by Arora et. al, in 2019, the lipid binding region of LPL actively interacts with the known inhibitor in the dimeric form. [2] This was established to be the only time that the homodimeric form was shown as an active lipase. The lid region residues Ile245, Ile249, V251, Ile252, Leu257, Val260, Leu263, and Val264, is found as an open conformation which is composed of two small alpha helices that reach out and away from the protein. The lid and lipid binding region create hydrophobic patches on the surface of lipoprotein lipase which are essential for by LPL.
 MechanismLipoprotein Lipase functions to catalyze the hydrolysis of one ester bond of triglycerides in order to remove one fatty acid tail and turn the triglyceride into a diglyceride. It does this by utilizing a simple serine hydrolase mechanism, in which it uses a composed of Asp183, His268, and Ser159 to catalyze the hydrolysis. His268 serves as a base catalyst by deprotonation of Ser159, which can then serve as the nucleophile. The transition state of the catalysis is stabilized by the backbone of Trp82 and Leu160 residues, forming the (Figure 2). The hydrolysis results in the formation of one free fatty acid and a glycerol with two fatty acid tails.  Relevance & DiseaseLPL is an extremely important enzyme, in that it is responsible for the proper breakdown of certain fats in the body. LPL breaks down triglycerides carried in chylomicrons, otherwise known as very low-density lipoproteins (VLDL). Chylomicrons carry digested fats in the form of triglycerides out of the small intestine and into the bloodstream. LPL recognizes the chylomicrons, and hydrolyzes the associated triglycerides.[3] When triglycerides are not broken down properly and are allowed to build up, they can lead to increased plasma triglyceride levels (hypertriglyceridemia) and cholesterol buildup. Hypertriglyceridemia is very unhealthy and is the leading cause of Coronary Artery Disease in America.[4] Cholesterol buildup is caused by excess fats (triglycerides) and is a similarly serious issue with regards to obesity and heart disease in the United States as it can lead to plaque buildup in arteries and veins, which restricts blood flow.[5] Chylomicronemia, which is defined as an excess of chylomicrons in the blood, is the disease characterized by the body being deficient in LPL resulting in persistent hypertriglyceridemia. This disease causes the body to be unable to digest very much ingested fats, and often leads to severe abdominal discomfort and several episodes of acute pancreatitis.[6] In short, without LPL in the body, triglycerides are unable to get broken down, and there is a much higher likelihood of developing coronary & metabolic based diseases. M404 MutationA mutation that is believed to cause chylomicronemia is known as M404R. Within this mutation, the methionine is replaced with a large and hydrophilic arginine. While this mutation does not impact LPL secretion, it does affect the formation of the LPL-GPIHBP1 complex. This mutation is known to impact LPL’s interaction with GPIHB1’s V121, E122, T124, and V126 residues. Given that the arginine disrupts the original stabilization of this complex, its occurrence disrupts the binding of the LPL-GPIHBP1 complex.
References
[1] [2] [3] [4] [5] (LPL GENERAL REFERENCE) [6] (LPL GENERAL REFERENCE BOOK IF NEEDED) [7] [8] [9] [10]
Student ContributorsGiselle Flores Dustin Soe Maggie Stopa
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