Cellular Interaction and Cytotoxicity of the Iowa Mutation of Apolipoprotein A-I (ApoA-IIowa) Amyloid Mediated by Sulfate Moieties of Heparan Sulfate

Kuwabara, Kaori; Nishitsuji, Kazuchika; Uchimura, Kenji; Hung, Shang‐Cheng; Mizuguchi, Makoto; Nakajima, Hiroyuki; Mikawa, Shiho; Kobayashi, N.; Saito, Hiroyuki; Sakashita, Naomi

doi:10.1074/jbc.m115.652545

Cited by 28 publications

(35 citation statements)

References 63 publications

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“…It should be noted that no enhancing effect of heparin was observed on fibril formation by the 1-83/ G26R variant (Fig. 1B) despite the finding that apoA-I 1-83/G26R fibrils interact with cell surface HS [22]. This discrepancy might be because heparin interacts differently with the N-terminal fragment of apoA-I in the different aggregated states (monomer, oligomer, or fibrils).…”

Section: Discussionmentioning

confidence: 80%

“…In general, it is thought that HS and heparin work as a scaffold to facilitate protein aggregation through electrostatic interactions with a basic motif in the protein . Recently, we demonstrated that cellular interaction and cytotoxicity of apoA‐I G26R amyloid fibrils are mediated by cell surface HS . Since certain amyloidogenic mutations such as G26R place additional arginine residue into the N‐terminal aggregation prone regions of apoA‐I , it is expected that these mutations would affect the process of amyloid fibril formation by apoA‐I through interactions with GAGs.…”

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confidence: 99%

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Heparin promotes fibril formation by the N‐terminal fragment of amyloidogenic apolipoprotein A‐I

et al. 2016

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Glycosaminoglycans are known to be associated with extracellular amyloid deposits of various amyloidogenic proteins. In this study, we found that the glycosaminoglycan heparin greatly accelerates the elongation step in fibril formation by the N-terminal 1-83 fragment of human apolipoprotein A-I (apoA-I), especially in the amyloidogenic W50R variant. Using fragment peptides, we demonstrate that heparin significantly promotes β-transition and fibril formation of the highly amyloidogenic region spanning residues 44-65 and colocalizes with fibrils formed by the W50R variant. These results suggest the possible role of glycosaminoglycans in fibril formation by amyloidogenic apoA-I variants.

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Section: Discussionmentioning

confidence: 80%

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confidence: 99%

Heparin promotes fibril formation by the N‐terminal fragment of amyloidogenic apolipoprotein A‐I

et al. 2016

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“…CHO cells are particularly suitable to this purpose and have been widely employed in SCFS applications (50,52,54,55). Furthermore, they have been also used as a model system to test protein aggregate toxicity (56)(57)(58), permitting a comparison of our data with those reported in the literature. The interaction between OA/OB species and the cell membrane was quantified as the mechanical work needed to detach a number of individual protein aggregate particles from the cell membrane.…”

Section: Introductionmentioning

confidence: 99%

Toxic HypF-N Oligomers Selectively Bind the Plasma Membrane to Impair Cell Adhesion Capability

Oropesa‐Nuñez

Keshavan

Dante

et al. 2018

Biophysical Journal

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The deposition of fibrillar protein aggregates in human organs is the hallmark of several pathological states, including highly debilitating neurodegenerative disorders and systemic amyloidoses. It is widely accepted that small oligomers arising as intermediates in the aggregation process, released by fibrils, or growing in secondary nucleation steps are the cytotoxic entities in protein-misfolding diseases, notably neurodegenerative conditions. Increasing evidence indicates that cytotoxicity is triggered by the interaction between nanosized protein aggregates and cell membranes, even though little information on the molecular details of such interaction is presently available. In this work, we propose what is, to our knowledge, a new approach, based on the use of single-cell force spectroscopy applied to multifunctional substrates, to study the interaction between protein oligomers, cell membranes, and/or the extracellular matrix. We compared the interaction of single Chinese hamster ovary cells with two types of oligomers (toxic and nontoxic) grown from the N-terminal domain of the Escherichia coli protein HypF. We were able to quantify the affinity between both oligomer type and the cell membrane by measuring the mechanical work needed to detach the cells from the aggregates, and we could discriminate the contributions of the membrane lipid and protein fractions to such affinity. The fundamental role of the ganglioside GM1 in the membrane-oligomers interaction was also highlighted. Finally, we observed that the binding of toxic oligomers to the cell membrane significantly affects the functionality of adhesion molecules such as Arg-Gly-Asp binding integrins, and that this effect requires the presence of the negatively charged sialic acid moiety of GM1.

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“…30 Interestingly, the GAG heparan sulfate prevented cytotoxic interactions of the G26R (Iowa) mutant with CHO cells. 31 Thirdly, oxidation of methionine residues has been shown to accelerate fibril deposition at normal physiological pH. 27,28 Activated Page 4 of 40…”

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Heparin and Methionine Oxidation Promote the Formation of Apolipoprotein A-I Amyloid Comprising α-Helical and β-Sheet Structures

et al. 2017

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Peptides derived from apolipoprotein A-I (apoA-I), the main component of high-density lipoprotein (HDL), constitute the main component of amyloid deposits that colocalize with atherosclerotic plaques. Here we investigate the molecular details of full-length, lipid-deprived apoA-I after assembly into insoluble aggregates under physiologically relevant conditions known to induce aggregation in vitro. Unmodified apoA-I is shown to remain soluble at pH 7 for at least 3 days, retaining its native α-helical-rich structure. Upon acidification to pH 4, apoA-I rapidly assembles into insoluble nonfibrillar aggregates lacking the characteristic cross-β features of amyloid. In the presence of heparin, the rate and thioflavin T responsiveness of the aggregates formed at pH 4 increase and short amyloid-like fibrils are observed, which give rise to amyloid-characteristic X-ray reflections at 4.7 and 10 Å. Solid-state nuclear magnetic resonance (SSNMR) and synchrotron radiation circular dichroism spectroscopy of fibrils formed in the presence of heparin show they retain some α-helical characteristics together with new β-sheet structures. Interestingly, SSNMR indicates a similar molecular structure of aggregates formed in the absence of heparin at pH 6 after oxidation of the three methionine residues, although their morphology is rather different from that of the heparin-derived fibrils. We propose a model for apoA-I aggregation in which perturbations of a four-helix bundle-like structure, induced by interactions of heparin or methionine oxidation, cause the partially helical N-terminal residues to disengage from the remaining, intact helices, thereby allowing self-assembly via β-strand associations.

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Cellular Interaction and Cytotoxicity of the Iowa Mutation of Apolipoprotein A-I (ApoA-IIowa) Amyloid Mediated by Sulfate Moieties of Heparan Sulfate

Cited by 28 publications

References 63 publications

Heparin promotes fibril formation by the N‐terminal fragment of amyloidogenic apolipoprotein A‐I

Heparin promotes fibril formation by the N‐terminal fragment of amyloidogenic apolipoprotein A‐I

Toxic HypF-N Oligomers Selectively Bind the Plasma Membrane to Impair Cell Adhesion Capability

Heparin and Methionine Oxidation Promote the Formation of Apolipoprotein A-I Amyloid Comprising α-Helical and β-Sheet Structures

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