Heparan Sulfate Dissociates Serum Amyloid A (SAA) from Acute-phase High-density Lipoprotein, Promoting SAA Aggregation

Department of Medical Biochemistry and Microbiology, The Biomedical Center, Husargatan 3, Box 582, Uppsala University, 751 23 Uppsala, Sweden.
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2012; 287(30):25669-77. DOI: 10.1074/jbc.M112.363895
Source: PubMed


Inflammation-related (AA) amyloidosis is a severe clinical disorder characterized by the systemic deposition of the acute-phase
reactant serum amyloid A (SAA). SAA is normally associated with the high-density lipoprotein (HDL) fraction in plasma, but
under yet unclear circumstances, the apolipoprotein is converted into amyloid fibrils. AA amyloid and heparan sulfate (HS)
display an intimate relationship in situ, suggesting a role for HS in the pathogenic process. This study reports that HS dissociates SAA from HDLs isolated from inflamed
mouse plasma. Application of surface plasmon resonance spectroscopy and molecular modeling suggests that HS simultaneously
binds to two apolipoproteins of HDL, SAA and ApoA-I, and thereby induce SAA dissociation. The activity requires a minimum
chain length of 12–14 sugar units, proposing an explanation to previous findings that short HS fragments preclude AA amyloidosis.
The results address the initial events in the pathogenesis of AA amyloidosis.

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Available from: Robert Kisilevsky, Jan 01, 2016
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    • "Studying a mechanism of human SAA-mediated AA-amyloid formation, Lu and coworkers (Lu et al. 2014) also investigated details of SAA binding to heparin sulfate (HS) and HDL. Previous studies have shown that binding of murine SAA to HS promotes HDL release from SAA and facilitates aggregation (Elimova et al. 2009; Noborn et al. 2012). In the work of Lu, the involvement of positively charged residues in HS binding was corroborated by structural and mutational analyses (Lu et al. 2014. "
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    ABSTRACT: Serum amyloid A (SAA) is a multifunctional acute-phase protein whose concentration in serum increases markedly following a number of chronic inflammatory and neoplastic diseases. Prolonged high SAA level may give rise to reactive systemic amyloid A (AA) amyloidosis, where the N-terminal segment of SAA is deposited as amyloid fibrils. Besides, recently, well-documented association of SAA with high-density lipoprotein or glycosaminoglycans, in particular heparin/heparin sulfate (HS), and specific interaction between SAA and human cystatin C (hCC), the ubiquitous inhibitor of cysteine proteases, was proved. Using a combination of selective proteolytic excision and high-resolution mass spectrometry, a hCC binding site in the SAA sequence was determined as SAA(86-104). The role of this SAA C-terminal fragment as a ligand-binding locus is still not clear. It was postulated important in native SAA folding and in pathogenesis of AA amyloidosis. In the search of conformational details of this SAA fragment, we did its structure and affinity studies, including its selected double/triple Pro→Ala variants. Our results clearly show that the SAA(86-104) 19-peptide has rather unordered structure with bends in its C-terminal part, which is consistent with the previous results relating to the whole protein. The results of affinity chromatography, fluorescent ELISA-like test, CD and NMR studies point to an importance of proline residues on structure of SAA(86-104). Conformational details of SAA fragment, responsible for hCC binding, may help to understand the objective of hCC-SAA complex formation and its importance for pathogenesis of reactive amyloid A amyloidosis. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Full-text · Article · Feb 2015 · Journal of Molecular Recognition
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    • "SAA synthesized in the local lung microenvironment may also generate HDL free aggregates, which unlike HDL bound SAA promotes inflammatory cytokine production through activation of PRRs such as ALX/FPR2. Furthermore, extracellular matrix products such as heparan sulfate fragments have recently been shown to promote dissociation of SAA bound to HDLs under acidic conditions (Noborn et al., 2012). Intriguingly, cigarette smoke exposure causes increased shedding and fragmentation of heparan sulfate (Yao et al., 2010), which may further facilitate the formation of active SAA aggregates in the lung. "
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    ABSTRACT: Neutrophilic inflammation persists in COPD despite best current therapies and it is particularly resistant to inhaled glucocorticosteroids. Persistent neutrophil activation not only contributes to matrix breakdown, but can maintain inflammation through the release of endogenous damage associated molecule patterns (DAMPs). Inhibiting excessive neutrophilic inflammation is challenging as many pathogen recognition receptors can initiate migration and the targeting of downstream signaling molecules may compromise essential host defense mechanisms. Here, we discuss new strategies to combat this inflammation in COPD by focusing on the anti-inflammatory role of ALX/FPR2 receptors. ALX/FPR2 is a promiscuous G-protein coupled receptor (GPCR) responding to lipid and peptide agonists that can either switch on acute inflammation or promote resolution of inflammation. We highlight this receptor as an emerging target in the pathogenesis of COPD because known ALX/FPR2 endogenous agonists are enriched in COPD. Serum Amyloid A (SAA) has recently been discovered to be abundantly expressed in COPD and is a potent ALX/FPR2 agonist that unlike almost all other inflammatory chemoattractants, is induced by glucocorticosteroids. SAA not only initiates lung inflammation via ALX/FPR2 but can allosterically modify this receptor so that it no longer transduces pro-resolving signals from endogenous lipoxins that would otherwise promote tissue healing. We propose that there is an imbalance in endogenous and microbial ALX/FPR2 receptor agonists in the inflamed COPD lung environment that oppose protective anti-inflammatory and pro-resolution pathways. These insights open the possibility of targeting ALX/FPR2 receptors using synthetic agonists to resolve persistent neutrophilic inflammation without compromising essential host defense mechanisms.
    Full-text · Article · Jul 2013 · Pharmacology [?] Therapeutics
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    • "In a previous study on a mouse isoform of SAA, we showed that Zn2+ binds to and stabilized the secondary, tertiary, and quaternary structure of mouse SAA2.2 while calcium destabilized SAA2.2 structure between 1 to 10 mM concentrations and induced its aggregation [47]. Heparan sulfate has also been shown to dissociate SAA from acute-phase HDL and promote its aggregation [48]. While the role of these co-factors and natural ligands remains to be completely elucidated, this study represents an important step in understanding the mechanism of hSAA1.1 oligomerization and fibrillation and may be useful for future studies of SAA-associated pathogenicity. "
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    ABSTRACT: The fibrillation of Serum Amyloid A (SAA) - a major acute phase protein - is believed to play a role in the disease Amyloid A (AA) Amyloidosis. To better understand the amyloid formation pathway of SAA, we characterized the oligomerization, misfolding, and aggregation of a disease-associated isoform of human SAA - human SAA1.1 (hSAA1.1) - using techniques ranging from circular dichroism spectroscopy to atomic force microscopy, fluorescence spectroscopy, immunoblot studies, solubility measurements, and seeding experiments. We found that hSAA1.1 formed alpha helix-rich, marginally stable oligomers in vitro on refolding and cross-beta-rich aggregates following incubation at 37°C. Strikingly, while hSAA1.1 was not highly amyloidogenic in vitro, the addition of a single N-terminal methionine residue significantly enhanced the fibrillation propensity of hSAA1.1 and modulated its fibrillation pathway. A deeper understanding of the oligomerization and fibrillation pathway of hSAA1.1 may help elucidate its pathological role.
    Full-text · Article · Jun 2013 · PLoS ONE
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