title: Genetic and structure-function studies of missense mutations in human endothelial lipase.
abstract: Endothelial lipase (EL) plays a pivotal role in HDL metabolism. We sought to characterize EL and its interaction with HDL as well as its natural variants genetically, functionally and structurally. We screened our biethnic population sample (n = 802) for selected missense mutations (n = 5) and identified T111I as the only common variant. Multiple linear regression analyses in Hispanic subjects revealed an unexpected association between T111I and elevated LDL-C (p-value = 0.012) and total cholesterol (p-value = 0.004). We examined lipase activity of selected missense mutants (n = 10) and found different impacts on EL function, ranging from normal to complete loss of activity. EL-HDL lipidomic analyses indicated that EL has a defined remodeling of HDL without exhaustion of the substrate and a distinct and preference for several fatty acids that are lipid mediators and known for their potent pro- and anti-inflammatory properties. Structural studies using homology modeling revealed a novel α/β motif in the C-domain, unique to EL. The EL dimer was found to have the flexibility to expand and to bind various sizes of HDL particles. The likely impact of the all known missense mutations (n = 18) on the structure of EL was examined using molecular modeling and the impact they may have on EL lipase activity using a novel structure-function slope based on their structural free energy differences. The results of this multidisciplinary approach delineated the impact of EL and its variants on HDL. Moreover, the results suggested EL to have the capacity to modulate vascular health through its role in fatty acid-based signaling pathways.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America. razzaghi_hamid@yahoo.com
authors.forename: Hamid
authors.initials: H
authors.lastname: Razzaghi
authors.forename: Anna
authors.initials: A
authors.lastname: Tempczyk-Russell
authors.forename: Kurt
authors.initials: K
authors.lastname: Haubold
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Santorico
authors.forename: Touraj
authors.initials: T
authors.lastname: Shokati
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.forename: Mair E A
authors.initials: ME
authors.lastname: Churchill
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism; D003120:Colorado; D004789:Enzyme Activation; D056726:Genetic Association Studies; D005838:Genotype; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism; D006630:Hispanic or Latino / Q000235:genetics; D006868:Hydrolysis; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008049:Lipase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010740:Phospholipases / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D016415:Sequence Alignment; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D008076:Cholesterol, HDL; D019812:Heparan Sulfate Proteoglycans; D002784:Cholesterol; D010740:Phospholipases; C410382:LIPG protein, human; D008049:Lipase
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