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Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis.

ABSTRACT: Serum amyloid A (SAA) represents an evolutionarily conserved family of inflammatory acute-phase proteins. It is also a major constituent of secondary amyloidosis. To understand its function and structural transition to amyloid, we determined a structure of human SAA1.1 in two crystal forms, representing a prototypic member of the family. Native SAA1.1 exists as a hexamer, with subunits displaying a unique four-helix bundle fold stabilized by its long C-terminal tail. Structure-based mutational studies revealed two positive-charge clusters, near the center and apex of the hexamer, that are involved in SAA association with heparin. The binding of high-density lipoprotein involves only the apex region of SAA and can be inhibited by heparin. Peptide amyloid formation assays identified the N-terminal helices 1 and 3 as amyloidogenic peptides of SAA1.1. Both peptides are secluded in the hexameric structure of SAA1.1, suggesting that the native SAA is nonpathogenic. Furthermore, dissociation of the SAA hexamer appears insufficient to initiate amyloidogenic transition, and proteolytic cleavage or removal of the C-terminal tail of SAA resulted in formation of various-sized structural aggregates containing ?5-nm regular repeating protofibril-like units. The combined structural and functional studies provide mechanistic insights into the pathogenic contribution of glycosaminoglycan in SAA1.1-mediated AA amyloid formation.

SUBMITTER: Lu J

PROVIDER: S-EPMC3986191 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis.

Lu Jinghua J Yu Yadong Y Zhu Iowis I Cheng Yifan Y Sun Peter D PD

Proceedings of the National Academy of Sciences of the United States of America 20140324 14

Serum amyloid A (SAA) represents an evolutionarily conserved family of inflammatory acute-phase proteins. It is also a major constituent of secondary amyloidosis. To understand its function and structural transition to amyloid, we determined a structure of human SAA1.1 in two crystal forms, representing a prototypic member of the family. Native SAA1.1 exists as a hexamer, with subunits displaying a unique four-helix bundle fold stabilized by its long C-terminal tail. Structure-based mutational s ...[more]

PMID: 24706838

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Project description:Numerous therapeutic agents and strategies were designed targeting the therapies of Alzheimer's disease, but many have been suspended due to their severe clinical side effects (such as encephalopathy) on patients. The attractiveness for small molecules with good biocompatibility is therefore restarted. Epigallocatechin-3-gallate (EGCG), extracted from green tea, is expected to be a promising small-molecule drug candidate, which can remodel the structure of preformed β-sheet-rich oligomers/fibrils and then effectively interfere with neurodegenerative processes. However, as the structure of non-fibrillary aggregates cannot be directly characterized, the atomic details of the underlying inhibitory and destructive mechanisms still remain elusive to date. Here, all-atom molecular dynamics simulations and experiments were carried out to elucidate the EGCG-induced remodeling mechanism of amyloid β (Aβ) fibrils. We showed that EGCG was indeed an effective Aβ fibril inhibitor. EGCG was capable of mediating conformational rearrangement of Aβ1-42 fibrils (from a β-sheet to a random coil structure) and triggering the disintegration of fibrils in a dose-dependent manner. EGCG redirected the structure of Aβ by breaking the β-sheet structure and hydrogen bonds between peptide chains within the Aβ protofibrils, especially the parallel β-strand (L17VFFAEDVGS26). Moreover, reduced solvent exposure and multisite binding patterns all tended to induce the conformation conversion of Aβ17-42 pentameric protofibrils, destroying pre-formed fibrils and inhibiting continued fibril growth. Detailed data analysis revealed that structural features of EGCG with abundant benzene ring and phenolic hydroxyl moieties preferentially interact with the parallel β-strands to effectually hinder the interaction of the interpeptide chain and the growth of the ordered β-sheet structure. Furthermore, experimental studies confirmed that EGCG was able to disaggregate the preformed fibrils and alter the protein structure. This study will enable a deeper understanding of fundamental principles for design of structural-based inhibitors.

Project description:RationaleStressful life events are suggested to contribute to the development of various pathologies, such as cardiovascular disorders, whose etiopathogenesis is highly associated with elevated levels of serum amyloid A (SAA) proteins. SAA synthesis in the liver is regulated by a complex network of cytokines acting independently or in concert with various hormones/stimulants including the stress-activated sympathetic nervous system.ObjectiveThis study aims to investigate the underlying mechanisms that regulate the stress-induced hepatic synthesis of SAA, with particular focus on adrenoceptors (AR), major components of the sympathoadrenal response to stress.Methods and resultsWe demonstrated that repeated stress elevates IL-1β, IL-6, and TNFα serum levels in mice, accompanied by increased synthesis and secretion of hepatic SAA1/2 and SAA3, an effect that was blocked by AR antagonists. Moreover, stimulation of α1- and β1/2-ARs mimics the stress effect on SAA1/2 regulation, whereas α2-AR stimulation exhibits a relatively weak impact on SAA. In support of the essential cytokine contribution in the AR-agonist induced SAA production is the fact that the anti-inflammatory drug, sodium salicylate, prevented the AR-stimulated hepatic SAA1/2 synthesis by reducing IL-1β levels, whereas IL-1β inhibition with Anakinra mimics this sodium salicylate preventive effect, thus indicating a crucial role for IL-1β. Interestingly, the AR-driven SAA3 synthesis was elevated by sodium salicylate in a TNFα-dependent way, supporting diverse and complex regulatory roles of cytokines in SAA production. In contrast to α1/α2-AR, the β1/2-AR-mediated SAA1/2 and SAA3 upregulation cannot be reversed by fenofibrate, a hypolipidemic drug with anti-inflammatory properties.ConclusionTaken together, these findings strongly support a critical role of the AR-stimulated inflammatory response in the hepatic SAA production under stressful conditions, highlighting distinct AR type-specific mechanisms that regulate the hepatic synthesis of SAA1/2 and SAA3.

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Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis.

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Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis.

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