Abstract 110: The Separation of Serum Amyloid A from HDL is Mediated by Heparan Sulfate Through Histidine Dependent Interactions: HDL Function is Enhanced but Amyloid-Fibrils may be the “Price to Pay”¼

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
John B Ancsin ◽  
Kim Munro ◽  
Shui-Pang Tam ◽  
Michael H Davidson
Keyword(s):  
Heparan Sulfate ◽  
Serum Amyloid A ◽  
Amyloid Fibrils ◽  
3D Structure ◽  
Serum Amyloid ◽  
Acidic Ph ◽  
Heparin Binding ◽  
Additional Time ◽  
Amyloid A ◽  
Hdl Function

Serum amyloid A (SAA) is an acute-phase protein that circulates bound to high density lipoprotein (HDL) and can influence HDL function as part of a poorly understood defense re-sponse to tissue trauma or infection. We have previously demonstrated that under mildly acidic pH the glycosaminoglycans, heparan sulfate (HS) and heparin can interact with HDL-SAA and cause SAA to dissociate from HDL. This remodeling improves HDL functionality but also predisposes SAA to form AA-amyloid fibrils. In this study we explore some potential pathophysiological conditions in vitro that could influence this HS/HDL-SAA remodeling process and the fate of SAA in vivo. SAA’s binding affinity for heparin was found to be enhanced by acidic pH and low concentrations of urea. The heparin dependent remodeling of HDL-SAA was promoted by the partial denaturation of HDL-SAA. Moreover, HDL-SAA remodeling was observed to follow a strict SAA:heparin stoichiometry and could be partially inhibited with a short heparin oligosaccharide of 8-sugar units. Evidence is also presented that once dissociated from HDL, SAA requires additional time to organize into Triton x-100 resistant amyloid-like structures. Circular dichroism spectroscopic analysis and in silico modeling of SAA’s ionizable residues highlights the importance of the histidine-36 within a highly conserved, pH-sensitive HS-binding site (HSBS-pH). A peptide containing the HSBS-pH sequence was demonstrated to have AA-amyloid seeding activity in a cell culture system. The recent determination of the 3D structure for human SAA1.1 has allowed the opportunity to re-assess and validate the HS/heparin binding sequences that had previously been identified biochemically with short synthetic peptides. We postulate that the dissociation of SAA from HDL takes place during the retro-endocytosis of HDL-SAA and is an important aspect of SAA function not previously appreciated.

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

2012 ◽  
Vol 287 (30) ◽  
pp. 25669-25677 ◽  
Author(s):  
Fredrik Noborn ◽  
John B. Ancsin ◽  
Wimal Ubhayasekera ◽  
Robert Kisilevsky ◽  
Jin-Ping Li
Keyword(s):  
High Density Lipoprotein ◽  
Heparan Sulfate ◽  
Acute Phase ◽  
Serum Amyloid A ◽  
Density Lipoprotein ◽  
High Density ◽  
Serum Amyloid ◽  
Amyloid A

scholarly journals Adenoviral expression of murine serum amyloid A proteins to study amyloid fibrillogenesis

1998 ◽  
Vol 332 (3) ◽  
pp. 721-728 ◽  
Author(s):  
Mark S. KINDY ◽  
Amy R. KING ◽  
Jin YU ◽  
Connie GERARDOT ◽  
Joel WHITLEY ◽  
...  
Keyword(s):  
Acute Phase ◽  
Half Life ◽  
Serum Amyloid A ◽  
Amyloid Fibrils ◽  
Serum Amyloid ◽  
Vector System ◽  
High Density Lipoproteins ◽  
Secondary Amyloidosis ◽  
Amyloid A ◽  
J Protein

Serum amyloid A (SAA) proteins are one of the most inducible acute-phase reactants and are precursors of secondary amyloidosis. In the mouse, SAA1 and SAA2 are induced in approximately equal quantities in response to amyloid induction models. These two isotypes differ in only 9 of 103 amino acid residues; however, only SAA2 is selectively deposited into amyloid fibrils. SAA expression in the CE/J mouse species is an exception in that gene duplication did not occur and the CE/J variant is a hybrid molecule sharing features of SAA1 and SAA2. However, even though it is more closely related to SAA2 it is not deposited as amyloid fibrils. We have developed an adenoviral vector system to overexpress SAA proteins in cell culture to determine the ability of these proteins to form amyloid fibrils, and to study the structural features in relation to amyloid formation. Both the SAA2 and CE/J SAA proteins were synthesized in large quantities and purified to homogeneity. Electron microscopic analysis of the SAA proteins revealed that the SAA2 protein was capable of forming amyloid fibrils, whereas the CE/J SAA was incapable. Radiolabelled SAAs were associated with normal or acute-phase high-density lipoproteins (HDLs); we examined them for their clearance from the circulation. In normal mice, SAA2 had a half-life of 70 min and CE/J SAA had a half-life of 120 min; however, in amyloid mice 50% of the SAA2 cleared in 55 min, compared with 135 min for the CE/J protein. When the SAA proteins were associated with acute-phase HDLs, SAA2 clearance was decreased to 60 min in normal mice compared with 30 min in amyloidogenic mice. Both normal and acute-phase HDLs were capable of depositing SAA2 into preformed amyloid fibrils, whereas the CE/J protein did not become associated with amyloid fibrils. This established approach opens the doors for large-scale SAA production and for the examination of specific amino acids involved in the fibrillogenic capability of the SAA2 molecule in vitro and in vivo.

scholarly journals The role of serum amyloid A and sphingosine-1-phosphate on high-density lipoprotein functionality

2015 ◽  
Vol 396 (6-7) ◽  
pp. 573-583 ◽  
Author(s):  
Nicole Prüfer ◽  
Burkhard Kleuser ◽  
Markus van der Giet
Keyword(s):  
High Density Lipoprotein ◽  
Acute Phase ◽  
Serum Amyloid A ◽  
Biological Activities ◽  
Density Lipoprotein ◽  
High Density ◽  
Serum Amyloid ◽  
Amyloid A ◽  
Hdl Function ◽  
Sphingosine 1 Phosphate

Abstract The high-density lipoprotein (HDL) is one of the most important endogenous cardiovascular protective markers. HDL is an attractive target in the search for new pharmaceutical therapies and in the prevention of cardiovascular events. Some of HDL’s anti-atherogenic properties are related to the signaling molecule sphingosine-1-phosphate (S1P), which plays an important role in vascular homeostasis. However, for different patient populations it seems more complicated. Significant changes in HDL’s protective potency are reduced under pathologic conditions and HDL might even serve as a proatherogenic particle. Under uremic conditions especially there is a change in the compounds associated with HDL. S1P is reduced and acute phase proteins such as serum amyloid A (SAA) are found to be elevated in HDL. The conversion of HDL in inflammation changes the functional properties of HDL. High amounts of SAA are associated with the occurrence of cardiovascular diseases such as atherosclerosis. SAA has potent pro-atherogenic properties, which may have impact on HDL’s biological functions, including cholesterol efflux capacity, antioxidative and anti-inflammatory activities. This review focuses on two molecules that affect the functionality of HDL. The balance between functional and dysfunctional HDL is disturbed after the loss of the protective sphingolipid molecule S1P and the accumulation of the acute-phase protein SAA. This review also summarizes the biological activities of lipid-free and lipid-bound SAA and its impact on HDL function.

Comparison of AA Amyloid Fibril Morphology and Serum Amyloid A Gene Sequence in 5 Animal Species

2020 ◽  
pp. 030098582097049
Author(s):  
Xuguang Lin ◽  
Masahiro Kuragano ◽  
Kenichi Watanabe ◽  
Kiyotaka Tokuraku
Keyword(s):  
Serum Amyloid A ◽  
Animal Species ◽  
Amyloid Fibrils ◽  
Serum Amyloid ◽  
Amyloid Proteins ◽  
Electron Microscopic ◽  
Amyloid A ◽  
Genetic Homology ◽  
Fibril Morphology

Amyloid fibrils are characterized by a linear morphology and a cross-β structure. Polymorphic and multiple fibril morphologies can be found when amyloid fibrils are extracted from amyloid-laden tissue. In this study, we report on the purification and transmission electron microscopic analysis of amyloid fibrils from 5 different animal species (mouse, cow, goat, dog, and camel) with AA amyloidosis. The results show that amyloid fibrils had a linear morphology with a cross-structure and irregular length in vivo. Although the fibrils from these different species showed highly similar conformations, there were significant differences in fibril width and crossover distance. We analyzed the sequences of homologous amyloid proteins and serum amyloid A, an evolutionarily conserved protein and a major amyloid precursor. We found 78.23% homology between the most distant amyloid proteins. The findings suggested similar fibril width and crossover distance in different animal species that displayed high homology of amyloid protein sequences. Dog and camel, as well as goat and cow, showed high genetic homology and similar fibril morphology. These data indicate that the fibrils from different animal species have similar genetic homology and morphology, which may provide a better understanding of the pathogenesis of amyloidosis.

scholarly journals Acute-phase high-density lipoprotein in the rat does not contain serum amyloid A protein

1987 ◽  
Vol 242 (1) ◽  
pp. 301-303 ◽  
Author(s):  
M L Baltz ◽  
I F Rowe ◽  
D Caspi ◽  
W G Turnell ◽  
M B Pepys
Keyword(s):  
High Density Lipoprotein ◽  
Acute Phase ◽  
Serum Amyloid A ◽  
Amyloid Fibrils ◽  
Density Lipoprotein ◽  
Lipid Binding ◽  
High Density ◽  
Serum Amyloid ◽  
Amyloid A ◽  
Serum Amyloid A Protein

Serum amyloid A protein (SAA) is an acute-phase apolipoprotein of high-density lipoprotein (HDL). Its N-terminal sequence is identical with that of amyloid A protein (AA), the subunit of AA amyloid fibrils. However, rats do not develop AA amyloidosis, and we report here that neither normal nor acute-phase rat HDL contains a protein corresponding to SAA of other species. mRNA coding for a sequence homologous with the C-terminal but not with the N-terminal part of human SAA is synthesized in greatly increased amounts in acute-phase rat liver. These observations indicate that the failure of rats to develop AA amyloid results from the absence of most of the AA-like part of their SAA-like protein, and that the N-terminal portion of SAA probably contains the lipid-binding sequences.

scholarly journals The Heparin/Heparan Sulfate-binding Site on Apo-serum Amyloid A

1999 ◽  
Vol 274 (11) ◽  
pp. 7172-7181 ◽  
Author(s):  
John B. Ancsin ◽  
Robert Kisilevsky
Keyword(s):  
Heparan Sulfate ◽  
Binding Site ◽  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Amyloid A
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