Lipid-apolipoprotein interactions in amyloid fibril formation and relevance to atherosclerosis

https://doi.org/10.1016/j.bbapap.2018.08.010Get rights and content

Highlights

  • •

    Apolipoproteins are prominent in the list of proteins known to form amyloid in vivo.

  • •

    Lipids alter the rate of formation and final structure of apolipoprotein amyloid.

  • •

    These effects may play roles in pathology of atherosclerosis and systemic amyloidoses.

  • •

    We review the complex effects of lipid on amyloid formation by apolipoprotein C-II.

Abstract

The apolipoprotein family is a set of highly conserved proteins characterized by the presence of amphipathic α-helical sequences that mediate lipid binding. Paradoxically, this family of proteins is also prominent among the proteins known to form amyloid fibrils, characterized by extensive cross-β structure. Several apolipoproteins including apolipoprotein (apo) A-I, apoA-II and apoC-II accumulate in amyloid deposits of atherosclerotic lesions. This review illustrates the role of lipid-apolipoprotein interactions in apolipoprotein folding and aggregation with a specific focus on human apoC-II, a well-studied member of the family. In the presence of high concentrations of micellar lipid mimetics apoC-II adopts a stable and predominantly α-helical structure, similar to other members of the family and presumed to be the structure of apoC-II in circulating plasma lipoproteins. In contrast, lipid-free apoC-II aggregates to form long amyloid fibrils with a twisted ribbon-like morphology. Detailed structural analyses identify a letter G-like conformation as the basic building block within these fibrils. Phospholipids at submicellar concentrations accelerate apoC-II fibril formation by promoting the formation of a discrete tetrameric intermediate. Conversely, several small molecule lipid-mimetics inhibit apoC-II fibril formation at submicellar concentrations, inducing well-defined dimers unable to further aggregate. Finally, low concentrations of phospholipid micelles and bilayers induce the slow formation of amyloid fibrils with distinct rod-like fibril morphology. These studies highlight the diversity of lipid effects on apolipoprotein amyloid formation and reveal a conformational adaptability that could underlie the widespread occurrence of apolipoproteins in amyloid deposits and atheroma.

Section snippets

Apolipoproteins and amyloid disease

Apolipoproteins form the protein component of plasma lipoproteins that transport lipids in the bloodstream. These proteins belong to a highly conserved family of lipid-binding proteins classified according to the presence of one or more class A amphipathic helical regions that mediate the interaction with lipids and lipid surfaces [1,2]. A paradoxical feature of this family of proteins is their disproportionate representation within the list of approximately 36 proteins known to form amyloid in

Lipid-bound apoC-II has α-helical structure

Circular dichroism and fluorescence emission spectra of lipid-free apoC-II at low concentration reveal a lack of significant secondary structure with only a gradual change induced by the addition of denaturing agents [6]. In contrast, in the presence of lipid micelles or vesicles a highly cooperative change occurs. These studies support NMR spectroscopy analyses of apoC-II bound to micelles of the lipid-like detergents sodium dodecyl sulphate (SDS) or dodecylphosphocholine (DPC) that indicate

Lipid-free apoC-II forms twisted ribbon amyloid fibrils

Lipid-free apoC-II readily self-assembles into homogeneous fibrils with increased β-structure and all the hallmarks of amyloid [31]. This self-assembly proceeds under physiological conditions, generating fibrils with “twisted-ribbon” morphology (Fig. 2a). X-ray diffraction patterns of aligned fibrils show a classical cross-β diffraction pattern with reflections at 4.67 Å and 9.46 Å. These spacings correspond to distances between β-strands in the fibril axis and the average spacing between

Sub-micellar lipid induces apoC-II tetramers

Investigations of the effect of individual lipids on the process of amyloid formation by apoC-II have explored the effects of the short-chain phospholipid 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC). This lipid has a critical micelle concentration of approximately 10 mM in 100 mM sodium phosphate at pH 7.4 [39]. Micellar concentrations of DHPC bind apoC-II and inhibit fibril formation while submicellar concentrations of DHPC enhance the rate of apoC-II amyloid formation as much as

Lipid-mimetics induce apoC-II dimers

The effects of lipids and their derivatives on apoC-II aggregation was extended by screening a library of diverse amphipathic lipids and detergents at submicellar concentrations for their effects on apoC-II fibril formation [43]. The initial screen identified a large number of compounds that activated apoC-II fibril formation and a similar number of compounds that inhibited apoC-II fibril formation. While there were no clear structural differences between activating or inhibiting molecules, a

Low concentrations of lipid micelles promote rod-like fibril formation

Studies on the effects of lipids on apoC-II show that high concentrations of micellar or vesicular phospholipids completely inhibit fibril formation [39]. However, in the presence of low concentrations of micellar or vesicular phospholipids, fibril formation is only partly inhibited with a two-phase growth pattern leading to the formation of fibrils with a distinct ‘rod-like’ morphology and displaying all of the hallmarks of amyloid fibrils [45,46] (Fig. 3). These straight, rod-like structures

Conclusions

This review presents compelling evidence of a pivotal role of lipids on the conformation and state of assembly of apoC-II. While the review is largely limited to apoC-II it is likely the general findings are equally applicable to other members of the apolipoprotein family and their common abilities to bind to lipid surfaces and to self-assemble into amyloid fibrils. Lipids are present at the site of apolipoprotein accumulation in atheroma where they can exert a direct effect on

Acknowledgments

M.D.W.G is the recipient of an Australian Research Council Future Fellowship (project number FT140100544). This work was supported by grants from the Australian Research Council and the National Health and Medical Research Council.

References (46)

  • L.M. Wilson et al.

    A structural core within apolipoprotein C-II amyloid fibrils identified using hydrogen exchange and proteolysis

    J. Mol. Biol.

    (2007)
  • C.L. Teoh et al.

    A structural model for apolipoprotein C-II amyloid fibrils: experimental characterization and molecular dynamics simulations

    J. Mol. Biol.

    (2011)
  • D.M. Hatters et al.

    Sub-micellar phospholipid accelerates amyloid formation by apolipoprotein C-II

    FEBS Lett.

    (2001)
  • T.M. Ryan et al.

    Phospholipids enhance nucleation but not elongation of apolipoprotein C-II amyloid fibrils

    J. Mol. Biol.

    (2010)
  • T.M. Ryan et al.

    Fluorescence detection of a lipid-induced tetrameric intermediate in amyloid fibril formation by apolipoprotein C-II

    J. Biol. Chem.

    (2008)
  • T.M. Ryan et al.

    High-affinity amphipathic modulators of amyloid fibril nucleation and elongation

    J. Mol. Biol.

    (2011)
  • T.M. Ryan et al.

    Apolipoprotein C-II adopts distinct structures in complex with Micellar and submicellar forms of the amyloid-inhibiting lipid-mimetic dodecylphosphocholine

    Biophys. J.

    (2016)
  • M.D. Griffin et al.

    Phospholipid interaction induces molecular-level polymorphism in apolipoprotein C-II amyloid fibrils via alternative assembly pathways

    J. Mol. Biol.

    (2008)
  • J.D. Sipe et al.

    Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines

    Amyloid

    (2016)
  • C.L. Teoh et al.

    Apolipoproteins and amyloid fibril formation in atherosclerosis

    Protein Cell

    (2011)
  • O. Gursky et al.

    Thermodynamic analysis of human plasma apolipoprotein C-1: high-temperature unfolding and low-temperature oligomer dissociation

    Biochemistry

    (1998)
  • D.M. Hatters et al.

    The structural basis for amyloid formation by plasma apolipoproteins: a review

    Eur. Biophys. J. Biophy.

    (2002)
  • D. Coriu et al.

    Hepatic amyloidosis resulting from deposition of the apolipoprotein A-I variant Leu75Pro

    Amyloid

    (2003)
    • View full text
    © 2018 Elsevier B.V. All rights reserved.