scholarly journals The effect of SARS-COV-2 Infections on Amyloid Formation of Serum Amyloid A

2021 ◽  
Author(s):  
Asis K Jana ◽  
Augustus B. Greenwood ◽  
Ulrich H.E. Hansmann
Keyword(s):  
Envelope Protein ◽  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Molecular Dynamic Simulations ◽  
Amyloid Formation ◽  
Dynamic Simulations ◽  
Amyloid A ◽  
The Stability ◽  
Inflammatory Syndrome

A marker for the severeness and disease progress of COVID-19 is overexpression of serum amyloid A (SAA) to levels that in other diseases are associated with a risk for SAA amyloidosis. This secondary illness is characterized by formation and deposition of SAA amyloids in blood vessels, causing inflammation, thrombosis and sometimes organ failure, with symptoms resembling the multisystem inflammatory syndrome (MIS) observed in some COVID-19 survivors. Hence, in order to understand better the danger of SAA amyloidosis in the context of COVID-19 we have used molecular dynamic simulations to study the effect of a SARS-COV-2 protein segment on SAA amyloid formation. We find that presence of the nine-residue segment SK9, located on the Envelope protein, increases the propensity for SAA fibril formation by three mechanisms: it reduces the stability of the lipid-transporting hexamer shifting the equilibrium toward monomers, it increases the frequency of aggregation-prone configurations in the resulting chains, and it raises the stability of SAA fibrils. Our results therefore suggest that SAA amyloidosis -related pathologies are a long-term risk of SARS-COV-2 infections.

scholarly journals Stability of Human Serum Amyloid A Fibrils

2020 ◽  
Author(s):  
Wenhua Wang ◽  
Ulrich H. E. Hansmann
Keyword(s):  
Serum Amyloid A ◽  
Salt Bridge ◽  
Fibril Formation ◽  
Serum Amyloid ◽  
Dynamic Simulations ◽  
Drug Candidates ◽  
Amyloid A ◽  
Fibril Structure ◽  
Acidic Conditions ◽  
The Stability

ABSTRACTIn systemic amyloidosis, Serum amyloid A (SAA) fibril deposits cause widespread damages to tissues and organs that eventually may lead to death. A therapeutically intervention therefore has either to dissolve these fibrils or inhibit their formation. However, only recently has the human SAA fibril structure be resolved at a resolution that is sufficient for development of drug candidates. Here, we use molecular dynamic simulations to probe the factors that modulate the stability of this fibril model. Our simulations suggest that fibril formation starts with the stacking of two misfolded monomers into metastable dimers, with the stacking depending on the N-terminal amyloidogenic regions of different chains forming anchors. The resulting dimers pack in a second step into a two-fold two-layer tetramer that is stable enough to nucleate fibril formation. The stability of the initial dimers is enhanced under acidic conditions by a strong salt bridge and side-chain hydrogen bond network in the C-terminal cavity (residues 23 - 51) but not affected by the presence of the disordered C-terminal tail.Table of Content Graphics

scholarly journals Cleavage, down-regulation and aggregation of serum amyloid A

2019 ◽  
Author(s):  
Wenhua Wang ◽  
Prabir Khatua ◽  
Ulrich H.E. Hansmann
Keyword(s):  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Amyloid Formation ◽  
Dynamic Simulations ◽  
Over Expression ◽  
Amyloid A ◽  
Serum Amyloid A Protein ◽  
Ph Increase ◽  
The One

AbstractVarious diseases cause over-expression of the serum amyloid A protein (SAA), which leads in some, but not all, cases to amyloidosis as a secondary disease. The response to the over-expression involves dissociation of SAA hexamer and subsequent cleavage of the released monomers, most commonly yielding fragments SAA1−76 of the full-sized SAA1−104. We report results from molecular dynamic simulations that probe the role of this cleavage for down-regulating activity and the concentration of SAA. We propose a mechanism that relies on two elements. First, the probability to assemble into hexamers is lower for the fragments than it is for the full-sized protein. Second, unlike other fragments SAA1−76 can switch between two distinct configurations. The first kind is easy to proteolyze (allowing a fast reduction of SAA concentration) but prone to aggregation, while the situation is opposite for the second kind. If the time scale for amyloid formation is longer than the one for proteolysis, the aggregation-prone species dominates. However, if environmental conditions such as low pH increase the risk of amyloid formation, the ensemble shifts toward the more protected form. We speculate that SAA amyloidosis is a failure of the switching mechanism leading to accumulation of the aggregation-prone species and subsequent amyloid formation.

scholarly journals Amyloid deposition in granuloma of tuberculosis patients: A pilot study

2021 ◽  
Author(s):  
Shreya Ghosh ◽  
Akansha Garg ◽  
Chayanika Kala ◽  
Ashwani Kumar Thakur
Keyword(s):  
Serum Amyloid A ◽  
Amyloid Deposition ◽  
Serum Amyloid ◽  
Secondary Amyloidosis ◽  
Amyloid Formation ◽  
Tuberculosis Patients ◽  
Amyloid A ◽  
Inflammatory Conditions ◽  
Amyloid Deposits ◽  
Serum Amyloid A Protein

AbstractThe formation of granuloma is one of the characteristic feature of tuberculosis. Besides, rise in the concentration of acute phase response proteins mainly serum amyloid A is the indicator for chronic inflammation associated with tuberculosis. Serum amyloid A drives secondary amyloidosis in tuberculosis and other chronic inflammatory conditions. The linkage between serum amyloid A (SAA) protein and amyloid deposition site is not well understood in tuberculosis and other chronic inflammatory conditions. We hypothesized that granuloma could be a potential site for amyloid deposition because of the presence of serum amyloid A protein and proteases that cleave SAA and trigger amyloid formation. Based on this hypothesis, for the first time we have shown the presence of amyloid deposits in the granuloma of tuberculosis patients using the gold standard, Congo red dye staining.

INCREASED SERUM AMYLOID A LEVELS REFLECT COLITIS SEVERITY AND PRECEDE AMYLOID FORMATION IN IL-2 KNOCKOUT MICE

Cytokine ◽  
2000 ◽  
Vol 12 (9) ◽  
pp. 1337-1347 ◽  
Author(s):  
Willem J.S de Villiers ◽  
Gary W Varilek ◽  
Frederick C de Beer ◽  
Jun-Tao Guo ◽  
Mark S Kindy
Keyword(s):  
Knockout Mice ◽  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Amyloid Formation ◽  
Amyloid A

scholarly journals Stability of the N-Terminal Helix and Its Role in Amyloid Formation of Serum Amyloid A

ACS Omega ◽  
2018 ◽  
Vol 3 (11) ◽  
pp. 16184-16190 ◽  
Author(s):  
Wenhua Wang ◽  
Wenhui Xi ◽  
Ulrich H. E. Hansmann
Keyword(s):  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Amyloid Formation ◽  
Amyloid A

scholarly journals Serum amyloid A binds to fibrin(ogen), promoting fibrin amyloid formation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Martin J. Page ◽  
Greig J. A. Thomson ◽  
J. Massimo Nunes ◽  
Anna-Mart Engelbrecht ◽  
Theo A Nell ◽  
...  
Keyword(s):  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Amyloid Formation ◽  
Amyloid A

Amyloid formation in the rat: Adenoviral expression of mouse serum amyloid A proteins

Amyloid ◽  
2000 ◽  
Vol 7 (1) ◽  
pp. 32-40 ◽  
Author(s):  
Jin Yu ◽  
Jun-Tao Guo ◽  
Hong Zhu ◽  
Mark S. Kindy
Keyword(s):  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Mouse Serum ◽  
Amyloid Formation ◽  
Amyloid A ◽  
Mouse Serum Amyloid

scholarly journals Use of Proteomics in the Study of Mastitis in Ewes

Pathogens ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 134 ◽  
Author(s):  
Angeliki I. Katsafadou ◽  
Natalia G. C. Vasileiou ◽  
George C. Fthenakis
Keyword(s):  
Staphylococcus Aureus ◽  
Clinical Studies ◽  
Serum Amyloid A ◽  
Diagnostic Techniques ◽  
Serum Amyloid ◽  
Mannheimia Haemolytica ◽  
Mycoplasma Agalactiae ◽  
Amyloid A ◽  
Streptococcus Uberis

The objective of this review is to describe the usage and applicability of proteomics technologies in the study of mastitis in ewes. In ewes, proteomics technologies have been employed for furthering knowledge in mastitis caused by various agents (Staphylococcus aureus, Staphylococcus chromogenes, Mannheimia haemolytica, Streptococcus uberis, Mycoplasma agalactiae). Studies have focused on improving knowledge regarding pathogenesis of the infections and identifying biomarkers for its diagnosis. Findings have revealed that ewes with mastitis mount a defence response, controlled by many proteins and over various mechanisms and pathways, which are interdependent at various points. Many proteins can participate in this process. Moreover, as the result of proteomics studies, cathelicidins and serum amyloid A have been identified as proteins that can be used as biomarkers for improved diagnosis of the disease. In the long term, proteomics will contribute to improvements in the elucidation of the pathogenesis of mastitis. Further in-depth investigations into the various proteomes and application of new methodological strategies in experimental and clinical studies will provide information about mastitis processes, which will be of benefit in controlling the disease. Improvement of diagnostic techniques, establishment of prognostic tools and development of vaccines are key areas for targeted research.

scholarly journals Small Peptides for Inhibiting Serum Amyloid A Aggregation

2021 ◽  
Author(s):  
Asis Jana ◽  
Augustus Greenwood ◽  
Ulrich H.E. Hansmann
Keyword(s):  
Amino Acids ◽  
Serum Amyloid A ◽  
Inflammatory Diseases ◽  
Life Time ◽  
Organ Damage ◽  
Serum Amyloid ◽  
Small Peptides ◽  
Dynamic Simulations ◽  
Drug Candidates ◽  
Amyloid A

Deposition of human Serum Amyloid A (SAA) amyloids in blood vessels, causing inflammation, thrombosis and eventually organ damage, are a commonly seen as a consequence of certain cancers and inflammatory diseases. Several attempts have been made to develop peptide-based drugs that inhibit or at least slow down SAA amyloidosis. We use extensive all-atom molecular dynamic simulations to compare three of these drug candidates for their ability to destabilize SAA fibrils, and to propose for the best candidate, the N-terminal sequence SAA1-5, a mechanism for inhibition. As the life-time of peptide drugs can be increased by replacing L-amino acids with their mirror D- amino acids, we have also studied corresponding D-peptides. We find that DRI-SAA1-5, formed of D-amino acids with the sequence of the peptide reversed, has similar inhibitory properties than the original L-peptide, and therefore may be a promising candidate for drugs targeting SAA amyloidosis.

scholarly journals Heterogeneity of human serum amyloid A protein. Five different variants from one individual demonstrated by cDNA sequence analysis

1990 ◽  
Vol 268 (1) ◽  
pp. 187-193 ◽  
Author(s):  
A Steinkasserer ◽  
E H Weiss ◽  
W Schwaeble ◽  
R P Linke
Keyword(s):  
Acute Phase ◽  
Serum Amyloid A ◽  
Northern Blot Analysis ◽  
Serum Amyloid ◽  
Amyloid A ◽  
Reactive Amyloidosis ◽  
Liver Cdna Library ◽  
Serum Amyloid A Protein ◽  
The Stability ◽  
Sensitive Marker

Serum amyloid A (SAA), a chemically polymorphic protein, is the most sensitive marker protein of the acute phase and the precursor of reactive amyloidosis, which is characterized by deposits of amyloid A protein (AA). We investigated the variability of the SAA gene family in one individual by sequencing 11 SAA-specific clones from an acute-phase-liver cDNA library. At least five different SAA variants were deduced from six different cDNAs. The 3′ untranslated gene segments fall into two groups, based on nucleotide sequence and variability in length. Various nucleotide and amino acid substitutions were found predominantly in the 3′ portion. Some of these substitutions are unique and increase the number of SAA variants in one individual to at least five. Moreover, genomic DNA of four individuals was examined by analysis of restriction-fragment length polymorphism. Besides two conserved strongly labelled bands, additional polymorphic bands were observed, indicating isotypic and/or allotypic SAA variations. Finally, three different mRNA species were detected by Northern-blot analysis, a finding that might be of relevance for the stability of SAA transcripts.

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