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Apolipoprotein C-II

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Geoffrey J. Howlett – 1st expert on this subject based on the ideXlab platform

  • Charge and charge-pair mutations alter the rate of assembly and structural properties of Apolipoprotein C-II amyloid fibrils.
    Biochemistry, 2015
    Co-Authors: Chai Lean Teoh, Geoffrey J. Howlett, Paul R. Gooley, Shuo Yang, Courtney O. Zlatic, Zachary Rosenes, Michael D. W. Griffin

    Abstract:

    The misfolding, aggregation, and accumulation of proteins as amyloid fibrils is a defining characteristic of several debilitating diseases. Human Apolipoprotein C-II (apoC-II) amyloid fibrils are representative of the fibrils formed by a number of plasma Apolipoproteins implicated in amyloid-related disease. Previous structural analyses identified a buried charge pair between residues K30 and D69 within apoC-II amyloid fibrils. We have investigated the effects of amino acid substitutions of these residues on apoC-II fibril formation. Two point mutations of apoC-II, D69K and K30D, as well as a reversed ion-pair mutant containing both mutations (KDDK) were generated. Fibril formation by the double mutant, apoC-II KDDK, and apoC-II D69K was enhanced compared to that of wild-type (WT) apoC-II, while apoC-II K30D lacked the ability to form fibrils under standard conditions. Structural analyses showed that WT apoC-II, apoC-II D69K, and apoC-II KDDK fibrils have similar secondary structures and morphologies. Siz…

  • The Role of Lipid in Misfolding and Amyloid Fibril Formation by Apolipoprotein C-II
    Advances in Experimental Medicine and Biology, 2015
    Co-Authors: Timothy M. Ryan, Geoffrey J. Howlett, Michael D. W. Griffin

    Abstract:

    Apolipoproteins are a key component of lipid transport in the circulatory system and share a number of structural features that facilitate this role. When bound to lipoprotein particles, these proteins are relatively stable. However, in the absence of lipids they display conformational instability and a propensity to aggregate into amyloid fibrils. Apolipoprotein C-II (apoC-II) is a member of the Apolipoprotein family that has been well characterised in terms of its misfolding and aggregation. In the absence of lipid, and at physiological ionic strength and pH, apoC-II readily forms amyloid fibrils with a twisted ribbon-like morphology that are amenable to a range of biophysical and structural analyses. Consistent with its lipid binding function, the misfolding and aggregation of apoC-II are substantially affected by the presence of lipid. Short-chain phospholipids at submicellar concentrations significantly accelerate amyloid formation by inducing a tetrameric form of apoC-II that can nucleate fibril aggregation. Conversely, phospholipid micelles and bilayers inhibit the formation of apoC-II ribbon-type fibrils, but induce slow formation of amyloid with a distinct straight fibril morphology. Our studies of the effects of lipid at each stage of amyloid formation, detailed in this chapter, have revealed complex behaviour dependent on the chemical nature of the lipid molecule, its association state, and the protein:lipid ratio.

  • Avoiding the oligomeric state: αB-crystallin inhibits fragmentation and induces dissociation of Apolipoprotein C-II amyloid fibrils
    The FASEB Journal, 2012
    Co-Authors: Katrina J. Binger, Geoffrey J. Howlett, John A. Carver, Heath Ecroyd, Shuo Yang, Michael D. W. Griffin

    Abstract:

    The in vivo aggregation of proteins into amyloid fibrils suggests that cellular mechanisms that normally prevent or reverse this aggregation have failed. The small heat-shock molecular chaperone protein αB-crystallin (αB-c) inhibits amyloid formation and colocalizes with amyloid plaques; however, the physiological reason for this localization remains unexplored. Here, using Apolipoprotein C-II (apoC-II) as a model fibril-forming system, we show that αB-c binds directly to mature amyloid fibrils (Kd 5.4 ± 0.5 μM). In doing so, αB-c stabilized the fibrils from dilution-induced fragmentation, halted elongation of partially formed fibrils, and promoted the dissociation of mature fibrils into soluble monomers. Moreover, in the absence of dilution, the association of αB-c with apoC-II fibrils induced a 14-fold increase in average aggregate size, resulting in large fibrillar tangles reminiscent of protein inclusions. We propose that the binding of αB-c to fibrils prevents fragmentation and mediates the lateral a…

Danny M. Hatters – 2nd expert on this subject based on the ideXlab platform

  • Phospholipid Complexation and Association with Apolipoprotein C-II: Insights from Mass Spectrometry
    Biophysical Journal, 2003
    Co-Authors: Charlotte L. Hanson, Leopold L. Ilag, Jonathan Malo, Danny M. Hatters, Geoffrey J. Howlett, Carol V. Robinson

    Abstract:

    The interactions between phospholipid molecules in suspensions have been studied by using mass spectrometry. Electrospray mass spectra of homogeneous preparations formed from three different phospholipid molecules demonstrate that under certain conditions interactions between 90 and 100 lipid molecules can be preserved. In the presence of Apolipoprotein C-II, a phospholipid binding protein, a series of lipid molecules and the protein were observed in complexes. The specificity of binding was demonstrated by proteolysis; the resulting mass spectra reveal lipid-bound peptides that encompass the proposed lipid-binding domain. The mass spectra of heterogeneous suspensions and their complexes with Apolipoprotein C-II demonstrate that the protein binds simultaneously to two different phospholipids. Moreover, when Apolipoprotein C-II is added to lipid suspensions formed with local concentrations of the same lipid molecule, the protein is capable of remodeling the distribution to form one that is closer to a statistical arrangement. These observations demonstrate a capacity for Apolipoprotein C-II to change the topology of the phospholipid surface. More generally, these results highlight the fact that mass spectrometry can be used to probe lipid interactions in both homogeneous and heterogeneous suspensions and demonstrate reorganization of the distribution of lipids upon surface binding of Apolipoprotein C-II.

  • The Circularization of Amyloid Fibrils Formed by Apolipoprotein C-II
    Biophysical Journal, 2003
    Co-Authors: Danny M. Hatters, Cait E. Macphee, Christopher A. Macraild, Rob D. Daniels, Walraj S. Gosal, Neil H. Thomson, Jonathan A. Jones, Jason J. Davis, Christopher M. Dobson, Geoffrey J. Howlett

    Abstract:

    Amyloid fibrils have historically been characterized by diagnostic dye-binding assays, their fibrillar morphology, and a “cross-β” x-ray diffraction pattern. Whereas the latter demonstrates that amyloid fibrils have a common β-sheet core structure, they display a substantial degree of morphological variation. One striking example is the remarkable ability of human Apolipoprotein C-II amyloid fibrils to circularize and form closed rings. Here we explore in detail the structure of apoC-II amyloid fibrils using electron microscopy, atomic force microscopy, and x-ray diffraction studies. Our results suggest a model for apoC-II fibrils as ribbons ∼2.1-nm thick and 13-nm wide with a helical repeat distance of 53 nm ± 12 nm. We propose that the ribbons are highly flexible with a persistence length of 36 nm. We use these observed biophysical properties to model the apoC-II amyloid fibrils either as wormlike chains or using a random-walk approach, and confirm that the probability of ring formation is critically dependent on the fibril flexibility. More generally, the ability of apoC-II fibrils to form rings also highlights the degree to which the common cross-β superstructure can, as a function of the protein constituent, give rise to great variation in the physical properties of amyloid fibrils.

  • Suppression of Apolipoprotein C‐II amyloid formation by the extracellular chaperone, clusterin
    FEBS Journal, 2002
    Co-Authors: Danny M. Hatters, Mark R. Wilson, Simon B. Easterbrook-smith, Geoffrey J. Howlett

    Abstract:

    The effect of the extracellular chaperone, clusterin, on amyloid fibril formation by lipid-free human Apolipoprotein C-II (apoC-II) was investigated. Sub-stoichiometric levels of clusterin, derived from either plasma or semen, potently inhibit amyloid formation by apoC-II. Inhibition is dependent on apoC-II concentration, with more effective inhibition by clusterin observed at lower concentrations of apoC-II. The average sedimentation coefficient of apoC-II fibrils formed from apoC-II (0.3 mg·mL−1) is reduced by coincubation with clusterin (10 µg·mL−1). In contrast, addition of clusterin (0.1 mg·mL−1) to preformed apoC-II amyloid fibrils (0.3 mg·mL−1) does not affect the size distribution after 2 days. This sedimentation velocity data suggests that clusterin inhibits fibril growth but does not promote fibril dissociation. Electron micrographs indicate similar morphologies for amyloid fibrils formed in the presence or absence of clusterin. The substoichiometric nature of the inhibition suggests that clusterin interacts with transient amyloid nuclei leading to dissociation of the monomeric subunits. We propose a general role for clusterin in suppressing the growth of extracellular amyloid.

Michael D. W. Griffin – 3rd expert on this subject based on the ideXlab platform

  • Apolipoprotein C-II Adopts Distinct Structures in Complex with Micellar and Submicellar Forms of the Amyloid-Inhibiting Lipid-Mimetic Dodecylphosphocholine.
    Biophysical Journal, 2016
    Co-Authors: Timothy M. Ryan, Michael D. W. Griffin, Duncan J. Mcgillivray, Robert Knott, Kathleen Wood, Colin L. Masters, Nigel Kirby, Cyril C. Curtain

    Abstract:

    Abstract The formation of amyloid deposits is a common feature of a broad range of diseases, including atherosclerosis, Alzheimer’s disease, and Parkinson’s disease. The basis and role of amyloid deposition in the pathogenesis of these diseases is still being defined, however an interesting feature of amyloidogenic proteins is that the majority of the pathologically associated proteins are involved in lipid homeostasis, be it in lipid transport, incorporation into membranes, or the regulation of lipid pathways. Thus, amyloid-forming proteins commonly bind lipids, and lipids are generally involved in the proper folding of these proteins. However, understanding of the basis for these lipid-related aspects of amyloidogenesis is lacking. Thus, we have used the Apolipoprotein C-II amyloid model system in conjunction with x-ray and neutron scattering analyses to address this problem. Apolipoprotein C-II is a well-studied model system of systemic amyloid fibril formation, with a clear and well-defined pathway for fibril formation, where the effects of lipid interaction are characterized, particularly for the lipid mimetic dodecylphosphocholine. We show that the micellar state of an inhibitory lipid can have a very significant effect on protein conformation, with micelles stabilizing a particular α -helical structure, whereas submicellar lipids stabilize a very different dimeric, α -helical structure. These results indicate that lipids may have an important role in the development and progression of amyloid-related diseases.

  • Charge and charge-pair mutations alter the rate of assembly and structural properties of Apolipoprotein C-II amyloid fibrils.
    Biochemistry, 2015
    Co-Authors: Chai Lean Teoh, Geoffrey J. Howlett, Paul R. Gooley, Shuo Yang, Courtney O. Zlatic, Zachary Rosenes, Michael D. W. Griffin

    Abstract:

    The misfolding, aggregation, and accumulation of proteins as amyloid fibrils is a defining characteristic of several debilitating diseases. Human Apolipoprotein C-II (apoC-II) amyloid fibrils are representative of the fibrils formed by a number of plasma Apolipoproteins implicated in amyloid-related disease. Previous structural analyses identified a buried charge pair between residues K30 and D69 within apoC-II amyloid fibrils. We have investigated the effects of amino acid substitutions of these residues on apoC-II fibril formation. Two point mutations of apoC-II, D69K and K30D, as well as a reversed ion-pair mutant containing both mutations (KDDK) were generated. Fibril formation by the double mutant, apoC-II KDDK, and apoC-II D69K was enhanced compared to that of wild-type (WT) apoC-II, while apoC-II K30D lacked the ability to form fibrils under standard conditions. Structural analyses showed that WT apoC-II, apoC-II D69K, and apoC-II KDDK fibrils have similar secondary structures and morphologies. Siz…

  • The Role of Lipid in Misfolding and Amyloid Fibril Formation by Apolipoprotein C-II
    Advances in Experimental Medicine and Biology, 2015
    Co-Authors: Timothy M. Ryan, Geoffrey J. Howlett, Michael D. W. Griffin

    Abstract:

    Apolipoproteins are a key component of lipid transport in the circulatory system and share a number of structural features that facilitate this role. When bound to lipoprotein particles, these proteins are relatively stable. However, in the absence of lipids they display conformational instability and a propensity to aggregate into amyloid fibrils. Apolipoprotein C-II (apoC-II) is a member of the Apolipoprotein family that has been well characterised in terms of its misfolding and aggregation. In the absence of lipid, and at physiological ionic strength and pH, apoC-II readily forms amyloid fibrils with a twisted ribbon-like morphology that are amenable to a range of biophysical and structural analyses. Consistent with its lipid binding function, the misfolding and aggregation of apoC-II are substantially affected by the presence of lipid. Short-chain phospholipids at submicellar concentrations significantly accelerate amyloid formation by inducing a tetrameric form of apoC-II that can nucleate fibril aggregation. Conversely, phospholipid micelles and bilayers inhibit the formation of apoC-II ribbon-type fibrils, but induce slow formation of amyloid with a distinct straight fibril morphology. Our studies of the effects of lipid at each stage of amyloid formation, detailed in this chapter, have revealed complex behaviour dependent on the chemical nature of the lipid molecule, its association state, and the protein:lipid ratio.