A Retained Secretory Signal Peptide Mediates High Density Lipoprotein (HDL) Assembly and Function of Haptoglobin-related Protein

Harrington, John M.; Nishanova, Tuiumkan; Pena, Savannah Rose; Hess, Matthew; Scelsi, Chris L.; Widener, Justin; Hajduk, Stephen L.

doi:10.1074/jbc.m114.567578

Cited by 21 publications

(11 citation statements)

References 40 publications

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“…The reason for this is not well understood, but it may be that the high radius of curvature in HDL creates phospholipid packing defects (Vedhachalam et al, 2007;Harrington et al, 2014), which more readily allows the insertion of hydrophobic signal peptides into the hydrophobic lipid core of HDL.…”

Section: Discussionmentioning

confidence: 99%

“…Other proteins with normally uncleaved signal peptides, such as paraoxonase 1 (Sorenson et al, 1999), apoM (Xu and Dahlbäck, 1999), and haptoglobin-related protein (Harrington et al, 2014), are also enriched on HDL. The reason for this is not well understood, but it may be that the high radius of curvature in HDL creates phospholipid packing defects (Vedhachalam et al, 2007;Harrington et al, 2014), which more readily allows the insertion of hydrophobic signal peptides into the hydrophobic lipid core of HDL.…”

Section: Discussionmentioning

confidence: 99%

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Creation of Apolipoprotein C-II (ApoC-II) Mutant Mice and Correction of Their Hypertriglyceridemia with an ApoC-II Mimetic Peptide

Sakurai¹,

Sakurai²,

Vaisman³

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Apolipoprotein C-II (apoC-II) is a cofactor for lipoprotein lipase, a plasma enzyme that hydrolyzes triglycerides (TGs). ApoC-II deficiency in humans results in hypertriglyceridemia. We used zinc finger nucleases to create Apoc2 mutant mice to investigate the use of C-II-a, a short apoC-II mimetic peptide, as a therapy for apoC-II deficiency. Mutant mice produced a form of apoC-II with an uncleaved signal peptide that preferentially binds high-density lipoproteins (HDLs) due to a 3-amino acid deletion at the signal peptide cleavage site. Homozygous Apoc2 mutant mice had increased plasma TG (757.5 6 281.2 mg/dl) and low HDL cholesterol (31.4 6 14.7 mg/dl) compared with wild-type mice (TG, 55.9 6 13.3 mg/dl; HDL cholesterol, 55.9 6 14.3 mg/dl). TGs were found in light (density , 1.063 g/ml) lipoproteins in the size range of verylow-density lipoprotein and chylomicron remnants (40-200 nm). Intravenous injection of C-II-a (0.2, 1, and 5 mmol/kg) reduced plasma TG in a dose-dependent manner, with a maximum decrease of 90% occurring 30 minutes after the high dose. Plasma TG did not return to baseline until 48 hours later. Similar results were found with subcutaneous or intramuscular injections. Plasma half-life of C-II-a is 1.33 6 0.72 hours, indicating that C-II-a only acutely activates lipolysis, and the sustained TG reduction is due to the relatively slow rate of new TG-rich lipoprotein synthesis. In summary, we describe a novel mouse model of apoC-II deficiency and show that an apoC-II mimetic peptide can reverse the hypertriglyceridemia in these mice, and thus could be a potential new therapy for apoC-II deficiency.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Creation of Apolipoprotein C-II (ApoC-II) Mutant Mice and Correction of Their Hypertriglyceridemia with an ApoC-II Mimetic Peptide

Sakurai¹,

Sakurai²,

Vaisman³

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…These results are rather surprising, because the SPs are generally cleaved off and degraded (34,35) after guiding the newly synthesized peptides to enter the ER. Very few SPs are retained and have been implicated in protein function such as that of the secretory protein HRP (46). The maintained pseudo-SP of the membrane protein CRF 2(a) R affects the receptor oligomerization (36,47).…”

Section: Discussionmentioning

confidence: 99%

GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors

Kalyanaraman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and predominantly assemble as heterotetramers in the brain. Recently, the crystal structures of homotetrameric GluA2 demonstrated that AMPARs are assembled with two pairs of conformationally distinct subunits, in a dimer of dimers formation. However, the structure of heteromeric AMPARs remains unclear. Guided by the GluA2 structure, we performed cysteine mutant cross-linking experiments in fulllength GluA1/A2, aiming to draw the heteromeric AMPAR architecture. We found that the amino-terminal domains determine the first level of heterodimer formation. When the dimers further assemble into tetramers, GluA1 and GluA2 subunits have preferred positions, possessing a 1-2-1-2 spatial assembly. By swapping the critical sequences, we surprisingly found that the spatial assembly pattern is controlled by the excisable signal peptides. Replacements with an unrelated GluK2 signal peptide demonstrated that GluA1 signal peptide plays a critical role in determining the spatial priority. Our study thus uncovers the spatial assembly of an important type of glutamate receptors in the brain and reveals a novel function of signal peptides.AMPA receptors | signal peptide | spatial assembly | stoichiometry

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“…More selectively, HDLs are also anchors for the organization the trypanosome lytic factor, a macromolecular complex containing Apo L1 and haptoglobin-related protein, highly lytic for Trypanosoma brucei [ 202 ]. This complex binds to HDL through an 18-amino acid signal peptide in its N-terminal region, interacting with lipids in the lipoprotein's monolayer [ 203 ]. This complex mediates hemoglobin binding and endocytosis of the parasite, facilitating its lysis and impeding progression of this infection [ 204 ].…”

Section: Proteomics and Lipidomics: A Focus On Hdlmentioning

confidence: 99%

Dysfunctional High-Density Lipoprotein: An Innovative Target for Proteomics and Lipidomics

et al. 2015

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High-Density Lipoprotein-Cholesterol (HDL-C) is regarded as an important protective factor against cardiovascular disease, with abundant evidence of an inverse relationship between its serum levels and risk of cardiovascular disease, as well as various antiatherogenic, antioxidant, and anti-inflammatory properties. Nevertheless, observations of hereditary syndromes featuring scant HDL-C concentration in absence of premature atherosclerotic disease suggest HDL-C levels may not be the best predictor of cardiovascular disease. Indeed, the beneficial effects of HDL may not depend solely on their concentration, but also on their quality. Distinct subfractions of this lipoprotein appear to be constituted by specific protein-lipid conglomerates necessary for different physiologic and pathophysiologic functions. However, in a chronic inflammatory microenvironment, diverse components of the HDL proteome and lipid core suffer alterations, which propel a shift towards a dysfunctional state, where HDL-C becomes proatherogenic, prooxidant, and proinflammatory. This heterogeneity highlights the need for further specialized molecular studies in this aspect, in order to achieve a better understanding of this dysfunctional state; with an emphasis on the potential role for proteomics and lipidomics as valuable methods in the search of novel therapeutic approaches for cardiovascular disease.

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A Retained Secretory Signal Peptide Mediates High Density Lipoprotein (HDL) Assembly and Function of Haptoglobin-related Protein

Cited by 21 publications

References 40 publications

Creation of Apolipoprotein C-II (ApoC-II) Mutant Mice and Correction of Their Hypertriglyceridemia with an ApoC-II Mimetic Peptide

Creation of Apolipoprotein C-II (ApoC-II) Mutant Mice and Correction of Their Hypertriglyceridemia with an ApoC-II Mimetic Peptide

GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors

Dysfunctional High-Density Lipoprotein: An Innovative Target for Proteomics and Lipidomics

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