Hydrogen/Deuterium Exchange and Molecular Dynamics Analysis of Amyloid Fibrils Formed by a D69K Charge-Pair Mutant of Human Apolipoprotein C-II

Mao, Yu; Zlatic, Courtney O.; Griffin, Michael D. W.; Howlett, Geoffrey J.; Todorova, Nevena; Yarovsky, Irene; Gooley, Paul R.

doi:10.1021/acs.biochem.5b00535

Cited by 15 publications

(32 citation statements)

References 36 publications

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“…In particular, electrostatic interactions, local hydrophobic contacts, and π stacking interfere with the well‐ordered core structure of Aβ fibrils, which is stabilized primarily by hydrogen bonds . Mutations can be introduced systematically along the entire peptide sequence, for example, by alanine or proline scans, or as point mutations introduced locally at structurally important intra‐ and interstrand contact points …”

Section: Discussionmentioning

confidence: 66%

“…Each mutation introduces modified physical forces that alter the local interaction pattern, which in turn lead to specific differences in fibril structure and fibrillation kinetics. Thus, not only familial variants, but also rationally designed peptides carrying mutations that introduce specific interactions and/or perturbations are a useful tool to investigate the thermodynamics and kinetics of fibril formation as well as the fibril morphology, local structure, and dynamics, as demonstrated in several studies . Such rationally designed polypeptide sequences that can probe the influence of a local specific physical force may help to understand the underlying principles of fibril formation.…”

Section: Introductionmentioning

confidence: 99%

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A Detailed Analysis of the Morphology of Fibrils of Selectively Mutated Amyloid β (1–40)

et al. 2016

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A small library of rationally designed amyloid β [Aβ(1-40)] peptide variants is generated, and the morphology of their fibrils is studied. In these molecules, the structurally important hydrophobic contact between phenylalanine 19 (F19) and leucine 34 (L34) is systematically mutated to introduce defined physical forces to act as specific internal constraints on amyloid formation. This Aβ(1-40) peptide library is used to study the fibril morphology of these variants by employing a comprehensive set of biophysical techniques including solution and solid-state NMR spectroscopy, AFM, fluorescence correlation spectroscopy, and XRD. Overall, the findings demonstrate that the introduction of significant local physical perturbations of a crucial early folding contact of Aβ(1-40) only results in minor alterations of the fibrillar morphology. The thermodynamically stable structure of mature Aβ fibrils proves to be relatively robust against the introduction of significantly altered molecular interaction patterns due to point mutations. This underlines that amyloid fibril formation is a highly generic process in protein misfolding that results in the formation of the thermodynamically most stable cross-β structure.

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Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

A Detailed Analysis of the Morphology of Fibrils of Selectively Mutated Amyloid β (1–40)

et al. 2016

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“…Thus, both the meridional and equatorial spacings are different for the twisted‐ribbon and rod‐like fibrillar structures. The two longer equatorial spacings (23.8 and 46.6 Å) for rod‐like fibrils are not observed in X‐ray diffraction patterns for aligned twisted‐ribbon fibrils and suggest the presence of more than two β‐sheets in the fibril cross section.…”

Section: Resultsmentioning

confidence: 89%

Polymorphism in disease‐related apolipoprotein C‐II amyloid fibrils: a structural model for rod‐like fibrils

et al. 2018

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Human apolipoprotein (apo) C-II is one of several plasma apolipoproteins that form amyloid deposits in vivo and is an independent risk factor for cardiovascular disease. Lipid-free apoC-II readily self-assembles into twisted-ribbon amyloid fibrils but forms straight, rod-like amyloid fibrils in the presence of low concentrations of micellar phospholipids. Charge mutations exerted significantly different effects on rod-like fibril formation compared to their effects on twisted-ribbon fibril formation. For instance, the double mutant, K30D-D69K apoC-II, readily formed twisted-ribbon fibrils, while the rate of rod-like fibril formation in the presence of micellar phospholipid was negligible. Structural analysis of rod-like apoC-II fibrils, using hydrogen-deuterium exchange and NMR analysis showed exchange protection consistent with a core cross-β structure comprising the C-terminal 58-76 region. Molecular dynamics simulations of fibril arrangements for this region favoured a parallel cross-β structure. X-ray fibre diffraction data for aligned rod-like fibrils showed a major meridional spacing at 4.6 Å and equatorial spacings at 9.7, 23.8 and 46.6 Å. The latter two equatorial spacings are not observed for aligned twisted-ribbon fibrils and are predicted for a model involving two cross-β fibrils in an off-set antiparallel structure with four apoC-II units per rise of the β-sheet. This model is consistent with the mutational effects on rod-like apoC-II fibril formation. The lipid-dependent polymorphisms exhibited by apoC-II fibrils could determine the properties of apoC-II in renal amyloid deposits and their potential role in the development of cardiovascular disease.

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“…[16][17][18][19][20] Researchers have shown that mutations introduced into lipid and lipoprotein lipase-binding portions of the Apo-CII protein can promote amyloid fibrillogenesis. [21][22][23] The E69V mutation discovered in this study is in the linker region, and isMD simulations suggest that the mutation can alter the conformation of the protein. Hence, it is possible that the E69V alteration mediates amyloid fibrillogenesis through destabilization of the mutant Apo-CII protein.…”

mentioning

confidence: 71%

“…This protein was previously shown to be amyloidogenic in animal models and in vitro studies. 16,17,[19][20][21][22][23] Thus, Apo-CII was considered a potential primary amyloid precursor protein in these cases.…”

Section: Concise Methodsmentioning

confidence: 99%

Novel Type of Renal Amyloidosis Derived from Apolipoprotein-CII

Nasr¹,

Dasari²,

Hasadsri³

et al. 2016

JASN

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Amyloidosis is characterized by extracellular deposition of misfolded proteins as insoluble fibrils. Most renal amyloidosis cases are Ig light chain, AA, or leukocyte chemotactic factor 2 amyloidosis, but rare hereditary forms can also involve the kidneys. Here, we describe the case of a 61-year-old woman who presented with nephrotic syndrome and renal impairment. Examination of the renal biopsy specimen revealed amyloidosis with predominant involvement of glomeruli and medullary interstitium. Proteomic analysis of Congo red-positive deposits detected large amounts of the Apo-CII protein. DNA sequencing of the APOC2 gene in the patient and one of her children detected a heterozygous c.206A→T transition, causing an E69V missense mutation. We also detected the mutant peptide in the proband's renal amyloid deposits. Using proteomics, we identified seven additional elderly patients with Apo-CII-rich amyloid deposits, all of whom had kidney involvement and histologically exhibited nodular glomerular involvement. Although prior in vitro studies have shown that Apo-CII can form amyloid fibrils and that certain mutations in this protein promote amyloid fibrillogenesis, there are no reports of this type of amyloidosis in humans. We propose that this study reveals a new form of hereditary amyloidosis (AApoCII) that is derived from the Apo-CII protein and appears to manifest in the elderly and preferentially affect the kidneys.

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Hydrogen/Deuterium Exchange and Molecular Dynamics Analysis of Amyloid Fibrils Formed by a D69K Charge-Pair Mutant of Human Apolipoprotein C-II

Cited by 15 publications

References 36 publications

A Detailed Analysis of the Morphology of Fibrils of Selectively Mutated Amyloid β (1–40)

A Detailed Analysis of the Morphology of Fibrils of Selectively Mutated Amyloid β (1–40)

Polymorphism in disease‐related apolipoprotein C‐II amyloid fibrils: a structural model for rod‐like fibrils

Novel Type of Renal Amyloidosis Derived from Apolipoprotein-CII

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