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  • J. Biol. Chem.-2015-Davies-7791-803

    Rights statement: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Unported License applies to Author Choice Articles

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Comparisons with amyloid-β reveal an aspartate residue that stabilizes fibrils of the aortic amyloid peptide medin

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Comparisons with amyloid-β reveal an aspartate residue that stabilizes fibrils of the aortic amyloid peptide medin. / Davies, Hannah; Madine, Jillian; Middleton, David.

In: Journal of Biological Chemistry, Vol. 290, 20.03.2015, p. 7791-7803.

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Davies, Hannah ; Madine, Jillian ; Middleton, David. / Comparisons with amyloid-β reveal an aspartate residue that stabilizes fibrils of the aortic amyloid peptide medin. In: Journal of Biological Chemistry. 2015 ; Vol. 290. pp. 7791-7803.

Bibtex

@article{858985fabe9b4c9781682d0e770b3883,
title = "Comparisons with amyloid-β reveal an aspartate residue that stabilizes fibrils of the aortic amyloid peptide medin",
abstract = "Aortic medial amyloid (AMA) is the most common localized human amyloid, occurring in virtually all of the Caucasian population over the age of 50. The main protein component of AMA, medin, readily assembles into amyloid-like fibrils in vitro. Despite the prevalence of AMA, little is known about the self-assembly mechanism of medin or the molecular architecture of the fibrils. The amino acid sequence of medin is strikingly similar to the sequence of the Alzheimer's disease (AD) amyloid-beta (Aβ) polypeptides around the structural turn region of Aβ where mutations associated with familial, early onset AD, have been identified. D25 and K30 of medin align with residues D23 and K28 of Aβ that are known to form a stabilizing salt bridge in some fibril morphologies. Here we show that substituting D25 of medin with asparagine (D25N) impedes assembly into fibrils and stabilizes non-cytotoxic oligomers. Wild-type medin, by contrast, aggregates into β-sheet rich amyloid-like fibrils within 50 h. A structural analysis of wild-type fibrils by solid-state NMR suggests a molecular repeat unit comprising at least two extended β-strands, separated by a turn stabilized by a D25-K30 salt-bridge. We propose that D25 drives the assembly of medin by stabilizing the fibrillar conformation of the peptide, and is thus reminiscent of the influence of D23 on the aggregation of Aβ. Pharmacological comparisons of wild-type medin and D25N will help to ascertain the pathological significance of this poorly under-stood protein.",
keywords = "amyloid, amyloid-beta (AB), homology modeling, protein misfolding, protein structure, site-directed mutagenesis, dipolar-assisted rotational resonance, rotational-echo double-resonance, salt bridge, solid-state nmr",
author = "Hannah Davies and Jillian Madine and David Middleton",
note = "Date of Acceptance: 22/01/2015 {\textcopyright} 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Unported License applies to Author Choice Articles",
year = "2015",
month = mar,
day = "20",
doi = "10.1074/jbc.M114.602177",
language = "English",
volume = "290",
pages = "7791--7803",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",

}

RIS

TY - JOUR

T1 - Comparisons with amyloid-β reveal an aspartate residue that stabilizes fibrils of the aortic amyloid peptide medin

AU - Davies, Hannah

AU - Madine, Jillian

AU - Middleton, David

N1 - Date of Acceptance: 22/01/2015 © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Unported License applies to Author Choice Articles

PY - 2015/3/20

Y1 - 2015/3/20

N2 - Aortic medial amyloid (AMA) is the most common localized human amyloid, occurring in virtually all of the Caucasian population over the age of 50. The main protein component of AMA, medin, readily assembles into amyloid-like fibrils in vitro. Despite the prevalence of AMA, little is known about the self-assembly mechanism of medin or the molecular architecture of the fibrils. The amino acid sequence of medin is strikingly similar to the sequence of the Alzheimer's disease (AD) amyloid-beta (Aβ) polypeptides around the structural turn region of Aβ where mutations associated with familial, early onset AD, have been identified. D25 and K30 of medin align with residues D23 and K28 of Aβ that are known to form a stabilizing salt bridge in some fibril morphologies. Here we show that substituting D25 of medin with asparagine (D25N) impedes assembly into fibrils and stabilizes non-cytotoxic oligomers. Wild-type medin, by contrast, aggregates into β-sheet rich amyloid-like fibrils within 50 h. A structural analysis of wild-type fibrils by solid-state NMR suggests a molecular repeat unit comprising at least two extended β-strands, separated by a turn stabilized by a D25-K30 salt-bridge. We propose that D25 drives the assembly of medin by stabilizing the fibrillar conformation of the peptide, and is thus reminiscent of the influence of D23 on the aggregation of Aβ. Pharmacological comparisons of wild-type medin and D25N will help to ascertain the pathological significance of this poorly under-stood protein.

AB - Aortic medial amyloid (AMA) is the most common localized human amyloid, occurring in virtually all of the Caucasian population over the age of 50. The main protein component of AMA, medin, readily assembles into amyloid-like fibrils in vitro. Despite the prevalence of AMA, little is known about the self-assembly mechanism of medin or the molecular architecture of the fibrils. The amino acid sequence of medin is strikingly similar to the sequence of the Alzheimer's disease (AD) amyloid-beta (Aβ) polypeptides around the structural turn region of Aβ where mutations associated with familial, early onset AD, have been identified. D25 and K30 of medin align with residues D23 and K28 of Aβ that are known to form a stabilizing salt bridge in some fibril morphologies. Here we show that substituting D25 of medin with asparagine (D25N) impedes assembly into fibrils and stabilizes non-cytotoxic oligomers. Wild-type medin, by contrast, aggregates into β-sheet rich amyloid-like fibrils within 50 h. A structural analysis of wild-type fibrils by solid-state NMR suggests a molecular repeat unit comprising at least two extended β-strands, separated by a turn stabilized by a D25-K30 salt-bridge. We propose that D25 drives the assembly of medin by stabilizing the fibrillar conformation of the peptide, and is thus reminiscent of the influence of D23 on the aggregation of Aβ. Pharmacological comparisons of wild-type medin and D25N will help to ascertain the pathological significance of this poorly under-stood protein.

KW - amyloid

KW - amyloid-beta (AB)

KW - homology modeling

KW - protein misfolding

KW - protein structure

KW - site-directed mutagenesis

KW - dipolar-assisted rotational resonance

KW - rotational-echo double-resonance

KW - salt bridge

KW - solid-state nmr

U2 - 10.1074/jbc.M114.602177

DO - 10.1074/jbc.M114.602177

M3 - Journal article

VL - 290

SP - 7791

EP - 7803

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

ER -