Structure–function analysis of D9N and N291S mutations in human lipoprotein lipase using molecular modelling

Razzaghi, Hamid; Day, Billy W.; McClure, Richard J.; Kamboh, M. Ilyas

doi:10.1016/s1093-3263(00)00096-6

Cited by 18 publications

(14 citation statements)

References 48 publications

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“…Similar to those previously reported, three known mutations of the LPL gene, Leu286Pro, Ala71Thr, and Asn291Ser, were associated with variable degrees of hyperlipidemia (15,21), supporting the hypothesis that Leu286Pro and Ala71Thr contribute to hypertriglyceridemia in these two pedigrees (pedigrees 1 and 3 in supplementary Table IIIa, IIIb). We now report three novel mutations of LPL, all of which negatively affect LPL activity and contribute to hypertriglyceridemia.…”

Section: Discussionsupporting

confidence: 88%

“…Two pedigrees showed the most common missense mutation, Asn291Ser (see supplementary Table IIIc, d). Similar to previous reports, this mutation in our subjects also appeared not to be consistently connected to hyperlipidemia (9,16,20,21).…”

Section: Molecular Screening Of the Lpl Gene In Hypertriglyceridemic supporting

confidence: 92%

“…Four of the variants were previously detected in exon 3 (Ala71Thr and Val108Val) and exon 6 (Leu286Pro and Asn291Ser) (9,15,16,(20)(21)(22). Three novel variants were detected in exon 6 (Lys312insC) and exon 8 (Thr361insA and Leu376Leu), including the compound heterozygotes Asn291Ser 1 Lys312insC.…”

Section: Molecular Screening Of the Lpl Gene In Hypertriglyceridemic mentioning

confidence: 94%

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Novel mutations of the lipoprotein lipase gene associated with hypertriglyceridemia in members of type 2 diabetic pedigrees

Ren

Luo

et al. 2007

Journal of Lipid Research

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Increased plasma triglyceride and free fatty acid levels are frequently associated with type 2 diabetes mellitus (T2DM). To test the hypothesis that LPL gene mutations contribute to the hypertriglyceridemia observed in members of T2DM pedigrees, we screened the LPL gene in 53 hypertriglyceridemic members of 26 families. Four known and three novel mutations were identified. All three novel mutations, Lys312insC, Thr361insA, and double mutation Lys312insC 1 Asn291Ser, are clinically associated with hypertriglyceridemia. In vitro mutagenesis and expression studies confirm that these variants are associated with a significant reduction in LPL activity. The modeled structures displaying the Lys312insC and Thr361insA mutations showed loss of the activity-related C-terminal domain in the LPL protein. Another novel double mutation, Lys312insC 1 Asn291Ser, resulted in the loss of the catalytic ability of LPL attributable to the complete loss of the C-terminal domain and alteration in the heparin association site. Thus, these novel mutations of the LPL gene contribute to the hypertriglyceridemia observed in members of type 2 diabetic

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Section: Discussionsupporting

confidence: 88%

Section: Molecular Screening Of the Lpl Gene In Hypertriglyceridemic supporting

confidence: 92%

Section: Molecular Screening Of the Lpl Gene In Hypertriglyceridemic mentioning

confidence: 94%

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Novel mutations of the lipoprotein lipase gene associated with hypertriglyceridemia in members of type 2 diabetic pedigrees

Ren

Luo

et al. 2007

Journal of Lipid Research

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“…These conflicting results suggest that apoC-II interacts simultaneously with complementary regions located in the N-terminal domain of one subunit and the C-terminal domain of the other. This hypothesis was suggested when Razzaghi et al demonstrated in a molecular modeling experiment that the C-terminal domain of apoC-II interacts with the interface of the N-and C-terminal domains of LPL and part of the lid surface [32].…”

Section: Discussionmentioning

confidence: 97%

Molecular modeling of the dimeric structure of human lipoprotein lipase and functional studies of the carboxyl‐terminal domain

Kobayashi

Nakajima

Inoue

2002

European Journal of Biochemistry

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Lipoprotein lipase (LPL) plays a key role in lipid metabolism. Molecular modeling of dimeric LPL was carried out using INSIGHT II based upon the crystal structures of human, porcine, and horse pancreatic lipase. The dimeric model reveals a saddle-shaped structure and the key heparinbinding residues in the amino-terminal domain located on the top of this saddle. The models of two dimeric conformations -a closed, inactive form and an open, active form -differ with respect to how surface-loop positions affect substrate access to the catalytic site. In the closed form, the surface loop covers the catalytic site, which becomes inaccessible to solvent. Large conformational changes in the open form, especially in the loop and carboxyl-terminal domain, allow substrate access to the active site. To dissect the structure-function relationships of the LPL carboxylterminal domain, several residues predicted by the model structure to be essential for the functions of heparin binding and substrate recognition were mutagenized. Arg405 plays an important role in heparin binding in the active dimer. Lys413/Lys414 or Lys414 regulates heparin affinity in both monomeric and dimeric forms. To evaluate the prediction that LPL forms a homodimer in a Ôhead-to-tailÕ orientation, two inactive LPL mutants -a catalytic site mutant (S132T) and a substrate-recognition mutant (W390A/W393A/ W394A) -were cotransfected into COS7 cells. Lipase activity could be recovered only when heterodimerization occurred in a head-to-tail orientation. After cotransfection, 50% of the wild-type lipase activity was recovered, indicating that lipase activity is determined by the interaction between the catalytic site on one subunit and the substraterecognition site on the other.Keywords: lipoprotein lipase; dimeric model structure; heparin binding; substrate recognition; catalytic activity.Lipoprotein lipase (LPL) belongs to a mammalian lipase family that includes pancreatic lipase (PL), hepatic lipase (HL), gastric lipase, and endothelial lipase [1,2]. The primary function of LPL is triglyceride hydrolysis in triglyceride-rich lipoproteins, such as chylomicron and very low density lipoprotein (VLDL) particles, which are converted to remnants. LPL is secreted from a variety of tissues, such as adipocyte, macrophage, and muscle cells, and is bound to the capillary bed of endothelium via cellular surface heparan sulfate proteoglycans (HSPG), a function reflected in LPL's strong affinity for heparin. LPL deficiencies in humans are manifested as severe hypertriglyceridemia [3-5] and arteriosclerosis [6]. Genetically engineered mice lacking LPL also exhibit hypertriglyceridemia. In addition to lipolytic activity, LPL functions as a ligand for lipoprotein receptors, such as low density lipoprotein (LDL) receptor, LDL receptor related protein (LRP), GP330/ LRP-2, and VLDL receptor [7][8][9][10][11].A model structure of LPL had previously been constructed, based on the crystal structure of human PL as a template [12]. The model structure exhibited two domainsa large N-t...

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“…It is further possible that the LPL D9N variant is in linkage disequilibrium with a polymorphism located within, or near, the peroxisome proliferator response element of the LPL promoter, whereby the N9 allele could mediate the functional responsiveness of LPL to fibrate therapy. Finally, the differences in response seen in carriers versus noncarriers may be attributable to distinct structural changes in LPL as a result of the aspartic acid-toasparagine amino acid substitution, a concept supported by the molecular modeling work of Razzaghi et al (44).…”

mentioning

confidence: 98%

Polymorphisms in the gene encoding lipoprotein lipase in men with low HDL-C and coronary heart disease

Brousseau

Goldkamp

Collins³

et al. 2004

Journal of Lipid Research

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Our goal was to further define the role of LPL gene polymorphisms in coronary heart disease (CHD) risk. We determined the frequencies of three LPL polymorphisms (D9N, N291S, and S447X) in 899 men from the Veterans Affairs HDL Intervention Trial (VA-HIT), a study that examined the potential benefits of increasing HDL with gemfibrozil in men with established CHD and low high density lipoprotein cholesterol (HDL-C; р 40 mg/dl), and compared them with those of men without CHD from the Framingham Offspring Study (FOS). In VA-HIT, genotype frequencies for LPL D9N, N291S, and S447X were 5.3, 4.5, and 13.0%, respectively. These values differed from those for men in FOS having an HDL-C of Ͼ 40, who had corresponding values of 3.2% ( P ‫؍‬ 0.06), 1.5% ( P Ͻ 0.01), and 18.2% ( P Ͻ 0.01). On gemfibrozil, carriers of the LPL N9 allele in VA-HIT had lower levels of large LDL ( ؊ 32%; P Ͻ 0.01) but higher levels of small, dense LDL ( ؉ 59%; P Ͻ 0.003) than did noncarriers. Consequently, mean LDL particle diameter was smaller in LPL N9 carriers than in noncarriers (20.14 ؎ 0.87 vs. 20.63 ؎ 0.80 nm; P Ͻ 0.003). In men with low HDL-C and CHD: 1 ) the LPL N9 and S291 alleles are more frequent than in CHD-free men with normal HDL-C, whereas the X447 allele is less frequent, and 2 ) the LPL N9 allele is associated with the LDL subclass response to gemfibrozil. -Brousseau,

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Structure–function analysis of D9N and N291S mutations in human lipoprotein lipase using molecular modelling

Cited by 18 publications

References 48 publications

Novel mutations of the lipoprotein lipase gene associated with hypertriglyceridemia in members of type 2 diabetic pedigrees

Novel mutations of the lipoprotein lipase gene associated with hypertriglyceridemia in members of type 2 diabetic pedigrees

Molecular modeling of the dimeric structure of human lipoprotein lipase and functional studies of the carboxyl‐terminal domain

Polymorphisms in the gene encoding lipoprotein lipase in men with low HDL-C and coronary heart disease

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