Aromatic residues in the C terminus of apolipoprotein C-III mediate lipid binding and LPL inhibition

Meyers, Nathan L.; Larsson, Mikael; Vorrsjö, Evelina; Olivecrona, Gunilla; Small, Donald

doi:10.1194/jlr.m071126

Cited by 20 publications

(19 citation statements)

References 60 publications

(120 reference statements)

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“…The C‐terminus of apo‐c3 has previously been found to be responsible for lipid binding, with the N‐terminus playing a limited secondary role. [ 40–42 ] These findings correlate with experimental evidence of the increased cellular uptake of C2GO, as compared to GO, hard protein corona. [ 15 ]…”

Section: Discussionsupporting

confidence: 60%

Nanomaterial Functionalization Modulates Hard Protein Corona Formation: Atomistic Simulations Applied to Graphitic Materials

al-Badri

Smith

Al‐Jamal

et al. 2021

Adv Materials Inter

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The protein corona is an obstacle to exploiting exotic properties of nanomaterials in clinical and biotechnological settings. The atomic‐scale dynamic formation of the protein corona at the bio‐nano interface is impenetrable using conventional experimental techniques. Here, molecular dynamics simulations are used to study the effect of graphene‐oxide (GO) functionalization on apolipoprotein‐cIII (apo‐c3) adsorption. An analysis pipeline is developed, encompassing binding energy calculations to protein structure analyses employing uniform manifold approximation and projection (UMAP) dimensionality reduction and clustering. It is found that apo‐c3 is denatured by GO adsorption, driven by the large energetic contributions of electrostatic interactions; enthalpic contributions of such binding events outweigh the intraprotein bond enthalpy required to maintain the protein tertiary structure. Through denaturing and exposing buried hydrophobic residues, the protein backbone is stabilized by forming β‐bridges, which serve as binding motifs for protein–protein interactions that drive further protein aggregation on the nanomaterial surface. In contrast, adsorption on double‐clickable azide‐ and alkyne‐double functionalized GO (C2GO), apo‐c3 largely retains its tertiary structure. Binding with the nanomaterial surface is dominated by weaker van der Waals interactions that are dispersed over the protein surface, where charged protein residues are sterically hindered by azide functional groups. The apo‐c3 C‐terminus remains unchanged upon C2GO adsorption, conserving its lipid‐binding function.

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Section: Discussionsupporting

confidence: 60%

Nanomaterial Functionalization Modulates Hard Protein Corona Formation: Atomistic Simulations Applied to Graphitic Materials

al-Badri

Smith

Al‐Jamal

et al. 2021

Adv Materials Inter

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“…Despite the fact that apoC-III was discovered more than 50 years ago ( 21 ), we still lack a detailed molecular understanding on how it interacts with lipoprotein particles, enzymes, and cell surface receptors ( 12 , 22 – 24 ). However, the two amphipathic helices, and the aromatic tryptophan residues in the carboxyl-terminal half of apoC-III seem to be important for its ability to interact with TRLs ( 25 ). Once synthesized, apoC-III can undergo posttranslational modification on threonine-74 resulting in three different glycoforms; unsialylated apoC-III 0 , monosialylated apoC-III 1 and disialylated apoC-III 2 ( 26 ).…”

Section: Structure and Regulation Of Apoc-iiimentioning

confidence: 99%

The Roles of ApoC-III on the Metabolism of Triglyceride-Rich Lipoproteins in Humans

2020

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Cardiovascular disease (CVD) is the leading cause of death globally. It is well-established based on evidence accrued during the last three decades that high plasma concentrations of cholesterol-rich atherogenic lipoproteins are causatively linked to CVD, and that lowering these reduces atherosclerotic cardiovascular events in humans (1-9). Historically, most attention has been on low-density lipoproteins (LDL) since these are the most abundant atherogenic lipoproteins in the circulation, and thus the main carrier of cholesterol into the artery wall. However, with the rise of obesity and insulin resistance in many populations, there is increasing interest in the role of triglyceride-rich lipoproteins (TRLs) and their metabolic remnants, with accumulating evidence showing they too are causatively linked to CVD. Plasma triglyceride, measured either in the fasting or non-fasting state, is a useful index of the abundance of TRLs and recent research into the biology and genetics of triglyceride heritability has provided new insight into the causal relationship of TRLs with CVD. Of the genetic factors known to influence plasma triglyceride levels variation in APOC3-the gene for apolipoprotein (apo) C-III-has emerged as being particularly important as a regulator of triglyceride transport and a novel therapeutic target to reduce dyslipidaemia and CVD risk (10).

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“…The structure and function of apoC-III have been studied for many years but we still do not have a clear picture of its many interactions with lipoprotein particles, other apolipoproteins, lipolytic enzymes (such as LPL), and cell surface receptors [ 1 – 4 ]. It has long been known that, as with other small apolipoproteins, apoC-III binds to the surface of lipoproteins by virtue of being able to form amphipathic helices along the peptide chain, and recent results indicate that aromatic residues in the C-terminal half of apoC-III are especially important in mediating binding to TRLs [ 5 ]. The protein undergoes posttranslational modification resulting in three different isoforms containing zero, one, or two sialic acids (termed apoC-III 0 , apoC-III 1 and apoC-III 2 ) [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Emerging Evidence that ApoC-III Inhibitors Provide Novel Options to Reduce the Residual CVD

Taskinen

Packard

Borén

2019

Curr Atheroscler Rep

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Purpose of Review Apolipoprotein C-III (apoC-III) is known to inhibit lipoprotein lipase (LPL) and function as an important regulator of triglyceride metabolism. In addition, apoC-III has also more recently been identified as an important risk factor for cardiovascular disease. This review summarizes the mechanisms by which apoC-III induces hypertriglyceridemia and promotes atherogenesis, as well as the findings from recent clinical trials using novel strategies for lowering apoC-III. Recent Findings Genetic studies have identified subjects with heterozygote loss-of-function (LOF) mutations in APOC3, the gene coding for apoC-III. Clinical characterization of these individuals shows that the LOF variants associate with a low-risk lipoprotein profile, in particular reduced plasma triglycerides. Recent results also show that complete deficiency of apoC-III is not a lethal mutation and is associated with very rapid lipolysis of plasma triglyceride-rich lipoproteins (TRL). Ongoing trials based on emerging gene-silencing technologies show that intervention markedly lowers apoC-III levels and, consequently, plasma triglyceride. Unexpectedly, the evidence points to apoC-III not only inhibiting LPL activity but also suppressing removal of TRLs by LPL-independent pathways. Summary Available data clearly show that apoC-III is an important cardiovascular risk factor and that lifelong deficiency of apoC-III is cardioprotective. Novel therapies have been developed, and results from recent clinical trials indicate that effective reduction of plasma triglycerides by inhibition of apoC-III might be a promising strategy in management of severe hypertriglyceridemia and, more generally, a novel approach to CHD prevention in those with elevated plasma triglyceride.

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Aromatic residues in the C terminus of apolipoprotein C-III mediate lipid binding and LPL inhibition

Cited by 20 publications

References 60 publications

Nanomaterial Functionalization Modulates Hard Protein Corona Formation: Atomistic Simulations Applied to Graphitic Materials

Nanomaterial Functionalization Modulates Hard Protein Corona Formation: Atomistic Simulations Applied to Graphitic Materials

The Roles of ApoC-III on the Metabolism of Triglyceride-Rich Lipoproteins in Humans

Emerging Evidence that ApoC-III Inhibitors Provide Novel Options to Reduce the Residual CVD

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