Role of the hydrophobic and charged residues in the 218–226 region of apoA-I in the biogenesis of HDL

Fotakis, Panagiotis; Kateifides, Andreas; Gkolfinopoulou, Christina; Georgiadou, Dimitra G.; Beck, Melissa J.; Gründler, Katharina; Chroni, Angeliki; Stratikos, Efstratios; Kardassis, Dimitris; Zannis, Vassilis I.

doi:10.1194/jlr.m038356

Cited by 13 publications

(21 citation statements)

References 39 publications

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“…Adenovirus-mediated gene transfer of these mutants in apoA-I À/À x apoE À/À mice (Fotakis et al 2013a, b) showed that compared to the WT apoA-I, the expression of an apoA-I[L218A/L219A/V221A/L222A] mutant decreased plasma cholesterol, apoA-I, and HDL cholesterol levels and generated preβ-and α4 HDL subpopulations (Fotakis et al 2013a) (Table 1 and Fig. 3a-g).…”

Section: Unique Mutations In Apoa-i May Affect Apoa-i/abca1mentioning

confidence: 94%

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HDL Biogenesis, Remodeling, and Catabolism

Zannis

Fotakis

Κούκος

et al. 2014

Handbook of Experimental Pharmacology

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In this chapter, we review how HDL is generated, remodeled, and catabolized in plasma. We describe key features of the proteins that participate in these processes, emphasizing how mutations in apolipoprotein A-I (apoA-I) and the other proteins affect HDL metabolism. The biogenesis of HDL initially requires functional interaction of apoA-I with the ATP-binding cassette transporter A1 (ABCA1) and subsequently interactions of the lipidated apoA-I forms with lecithin/cholesterol acyltransferase (LCAT). Mutations in these proteins either prevent or impair the formation and possibly the functionality of HDL. Remodeling and catabolism of HDL is the result of interactions of HDL with cell receptors and other membrane and plasma proteins including hepatic lipase (HL), endothelial lipase (EL), phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), apolipoprotein M (apoM), scavenger receptor class B type I (SR-BI), ATP-binding cassette transporter G1 (ABCG1), the F1 subunit of ATPase (Ecto F1-ATPase), and the cubulin/megalin receptor. Similarly to apoA-I, apolipoprotein E and apolipoprotein A-IV were shown to form discrete HDL particles containing these apolipoproteins which may have important but still unexplored functions. Furthermore, several plasma proteins were found associated with HDL and may modulate its biological functions. The effect of these proteins on the functionality of HDL is the topic of ongoing research.

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Section: Unique Mutations In Apoa-i May Affect Apoa-i/abca1mentioning

confidence: 94%

“…As explained later, such particles are found in the plasma of mice expressing C-terminal mutants and may be created by mechanisms that involve nonproductive interactions between ABCA1 and apoA-I (Chroni et al 2007;Fotakis et al 2013a).…”

Section: Interaction Of Apoa-i With Abca1 In Vivo Initiatesmentioning

confidence: 98%

HDL Biogenesis, Remodeling, and Catabolism

Zannis

Fotakis

Κούκος

et al. 2014

Handbook of Experimental Pharmacology

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“…In contrast to the apoA-I[218-222] mutant described in the preceding article ( 8 ), the defective HDL phenotype caused by the 225-230 mutations could be corrected by coexpression of the apoA-I mutant and human LCAT.…”

Section: Fractionation Of Plasma Of Apoa-i ؊ / ؊ Mice Expressing the mentioning

confidence: 57%

“…An abnormality that persisted in apoA-I Ϫ / Ϫ × apoE Ϫ / Ϫ mice expressing the apoA-I[225-230] mutant was the presence of VLDL-, IDL-, and LDLsized particles in the HDL fractions. The present study in combination with the preceding study ( 8 ) shows the essential role of eight hydrophobic residues present in the 218-230 region of apoA-I for the structure and function of apoA-I and its ability to form HDL. The two studies enhance our understanding of the complex factors that contribute to the correct extracellular assembly, maturation, and proteomic composition of HDL.…”

Section: Lcat Corrects the Aberrant Hdl Phenotype Caused By The Apoa-mentioning

confidence: 71%

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Significance of the hydrophobic residues 225–230 of apoA-I for the biogenesis of HDL

Fotakis

Tiniakou

Kateifides

et al. 2013

Journal of Lipid Research

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and the biogenesis of HDL but did not identify the apoA-I residues involved ( 1, 2 ). Other studies also showed the importance of the C-terminal region for the structure of apoA-I ( 3-5 ) as well as for other functions of apoA-I ( 6, 7 ). In the preceding article, we investigated the role of the hydrophobic residues L218, L219, V221, and L222 and the charged residues E223 and K226 on the structure and functions of apoA-I and their contribution to the biogenesis of HDL ( 8 ). These studies showed that substitution of the hydrophobic residues L218, L219, V221, and L222 of apoA-I by alanines inhibits the biogenesis and maturation of HDL and generates a phenotype that cannot be corrected by LCAT. Expression of E223 and K226 caused fewer but discrete alterations in the HDL phenotype.The rationale for the present study was that the 225-230 region of apoA-I contains four additional hydrophobic residues that may be equally signifi cant for its structure and functions. For this reason, we used gene transfer in two mouse models as well as biochemical and biophysical analyses to study the impact of substitutions of residues F225, V227, F229, and L230 by alanines on the structure and functions of apoA-I and their impact on the biogenesis of HDL. In vitro experiments showed that the apoA-I[225-230] mutations affected the structure of apoA-I, diminished its capacity to promote ABCA1-mediated cholesterol effl ux, and decreased moderately its ability to activate LCAT. Gene transfer of the apoA-I mutant in apoA-I Previous studies by us showed the overall importance of the 220-231 region of apoA-I for apoA-I/ABCA1 interactions

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Evolutionary and structural constraints influencing apolipoprotein A‐I amyloid behavior

et al. 2021

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Aggregation-prone region 1 (APR1), comprising residues 14-19, is consistently conserved during the evolutionary history of Apolipoprotein A-I. • APR1 contributes to thermal stability of the ɑ-helix bundle in the full-length Apolipoprotein A-I model. • Amyloid variants introduce a destabilizing effect on the monomer structure of Apolipoprotein A-I, in contrast to HDL-deficiency and naturally-occurring variants, which are nearly neutral. • During molecular dynamics simulations, G26R amyloidogenic mutant lead to the partial unfolding of ɑ-helix bundle and exposure of APR1..

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Role of the hydrophobic and charged residues in the 218–226 region of apoA-I in the biogenesis of HDL

Cited by 13 publications

References 39 publications

HDL Biogenesis, Remodeling, and Catabolism

HDL Biogenesis, Remodeling, and Catabolism

Significance of the hydrophobic residues 225–230 of apoA-I for the biogenesis of HDL

Evolutionary and structural constraints influencing apolipoprotein A‐I amyloid behavior

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