A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state

Melchior, John T.; Walker, Ryan G.; Cooke, Allison L; Morris, Jamie; Castleberry, Mark; Thompson, Thomas B.; Jones, Martin K.; Song, Hyun Deok; Rye, Kerry‐Anne; Oda, Michael N.; Sorci‐Thomas, Mary G.; Thomas, Michael J.; Heinecke, Jay W.; Mei, Xiaohu; Atkinson, David; Segrest, Jere P.; Lund‐Katz, Sissel; Phillips, Michael C.; Davidson, W. Sean

doi:10.1038/nsmb.3501

Cited by 59 publications

(85 citation statements)

References 63 publications

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“…S6). The published solution structure of the monomeric nonoxidized protein presents a highly unstructured C‐terminal domain (82, 91). Nevertheless, our analysis of the INEPT spectra of the aggregated samples indicates that the number of highly dynamic and unstructured residues is relatively small.…”

Section: Resultsmentioning

confidence: 99%

Methionine oxidized apolipoprotein A‐I at the crossroads of HDL biogenesis and amyloid formation

Witkowski¹,

Chan²,

Boatz

et al. 2018

FASEB j.

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Apolipoprotein A-I (apoA-I) shares with other exchangeable apolipoproteins a high level of structural plasticity. In the lipid-free state, the apolipoprotein amphipathic α-helices interact intra- and intermolecularly, providing structural stabilization by self-association. We have reported that lipid-free apoA-I becomes amyloidogenic upon physiologically relevant (myeloperoxidase-mediated) Met oxidation. In this study, we established that Met oxidation promotes amyloidogenesis by reducing the stability of apoA-I monomers and irreversibly disrupting self-association. The oxidized apoA-I monomers also exhibited increased cellular cholesterol release capacity and stronger association with macrophages, compared to nonoxidized apoA-I. Of physiologic relevance, preformed oxidized apoA-I amyloid fibrils induced amyloid formation in nonoxidized apoA-I. This process was enhanced when self-association of nonoxidized apoA-I was disrupted by thermal treatment. Solid state NMR analysis revealed that aggregates formed by seeded nonoxidized apoA-I were structurally similar to those formed by the oxidized protein, featuring a β-structure-rich amyloid fold alongside α-helices retained from the native state. In atherosclerotic lesions, the conditions that promote apoA-I amyloid formation are readily available: myeloperoxidase, active oxygen species, low pH, and high concentration of lipid-free apoA-I. Our results suggest that even partial Met oxidation of apoA-I can nucleate amyloidogenesis, thus sequestering and inactivating otherwise antiatherogenic and HDL-forming apoA-I.-Witkowski, A., Chan, G. K. L., Boatz, J. C., Li, N. J., Inoue, A. P., Wong, J. C., van der Wel, P. C. A., Cavigiolio, G. Methionine oxidized apolipoprotein A-I at the crossroads of HDL biogenesis and amyloid formation.

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Section: Resultsmentioning

confidence: 99%

Methionine oxidized apolipoprotein A‐I at the crossroads of HDL biogenesis and amyloid formation

Witkowski¹,

Chan²,

Boatz

et al. 2018

FASEB j.

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“…We propose a model for regulation of apoA1's helix bundle unfolding based on the C isoform crystal structure (6), the "consensus" model of apoA1 (7), and our current findings. The crystal structure places Trp8 (W8) at the start of H1 (6), which we propose to be a central player that acts as a "node" to stabilize the helix bundle.…”

Section: Discussionmentioning

confidence: 74%

“…Thus, the Trp8 substitution W8A or deletion of residues 1-8 removes the "node" and allows the helical bundle to unfold easier. In the apoA1 structure consensus model, the C-terminus is adjacent to the N-terminus ( Figure 6A, B) (7). This interaction is supported by numerous lysine/amine crosslinking studies using full length, monomeric, lipid-free apoA1, including cross links between the following lysine pairs (first lysine/amine in the N-terminus/hairpin bundle between residues 1 and 115 x second lysine in the C-terminus between (7,(18)(19)(20).…”

Section: Discussionmentioning

confidence: 77%

“…The C apoA1 crystal structure (Protein Data Bank accession number 3r2p) (6) and the full length apoA1 consensus model (downloaded from htpp://homepages.uc.edu/~davidswm/structures.html) (7) were visualized and customized using PyMOL 2.1.1 (Incentive Product).…”

Section: Apoa1 Structural Modelingmentioning

confidence: 99%

“…This crystal structure includes a folded mostly alpha-helical bundle extending from residue 8-112. The apoA1 "consensus" model, built from the crystal structure along with chemical linking, and other biophysical and structural data from the past four decades, has labeled the individual helixes: H1 (residues 8-32), H2 (37-45), H3 (54-64), H4 (68-78), H5 (81-115), and H6 (148-179) (7). It has long been appreciated that the C-terminal truncation of residues 183-243 (called hereafter the C isoform) is dysfunctional in regard to both its DMPC solubilization and ABCA1-dependent lipid acceptor activities (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

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First eight residues of apolipoprotein A-I mediate the C-terminus control of helical bundle unfolding and its lipidation

Brubaker

Lorkowski

Gulshan

et al. 2019

Preprint

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The crystal structure of a C-terminal deletion of apolipoprotein A-I (apoA1) shows a large helical bundle structure in the amino half of the protein, from residues 8 to 115. Using site directed mutagenesis, guanidine or thermal denaturation, cell free liposome clearance, and cellular ABCA1-mediated cholesterol efflux assays, we demonstrate that apoA1 lipidation can occur when the barrier to this bundle unfolding is lowered. The absence of the C-terminus renders the bundle harder to unfold resulting in loss of apoA1 lipidation that can be reversed by point mutations, such as Trp8Ala, and by truncations as short as 8 residues in the amino terminus, both of which lower the barrier to helical bundle unfolding. Locking the bundle via a disulfide bond leads to loss of apoA1 lipidation. We propose a model in which the Cterminus acts on the N-terminus to destabilize helical bundle. Upon lipid binding to the C-terminus, Trp8 is displaced from its interaction with Phe57, Arg61, Leu64, Val67, Phe71, and Trp72 to destabilize the bundle. However, when the C-terminus is deleted, Trp8 cannot be displaced, the bundle cannot unfold, and apoA1 cannot be lipidated.

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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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A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state

Cited by 59 publications

References 63 publications

Methionine oxidized apolipoprotein A‐I at the crossroads of HDL biogenesis and amyloid formation

Methionine oxidized apolipoprotein A‐I at the crossroads of HDL biogenesis and amyloid formation

First eight residues of apolipoprotein A-I mediate the C-terminus control of helical bundle unfolding and its lipidation

Evolutionary and structural constraints influencing apolipoprotein A‐I amyloid behavior

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