Stability of Human Serum Amyloid A Fibrils

Mapping Intimacies ◽

10.1101/2020.09.10.291948 ◽

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

Download Full-text

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

10.1101/2021.05.18.444723 ◽

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.

Download Full-text

Small Peptides for Inhibiting Serum Amyloid A Aggregation

10.33774/chemrxiv-2021-m9c8j ◽

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.

Download Full-text

The potential role of glycosaminoglycans in serum amyloid A fibril formation by in silico approaches

Matrix Biology Plus ◽

10.1016/j.mbplus.2021.100080 ◽

2021 ◽

pp. 100080

Author(s):

Martyna Maszota-Zieleniak ◽

Annemarie Danielsson ◽

Sergey A. Samsonov

Keyword(s):

In Silico ◽

Serum Amyloid A ◽

Potential Role ◽

Fibril Formation ◽

Serum Amyloid ◽

Amyloid A

Download Full-text

Structural requirements of glycosaminoglycans for facilitating amyloid fibril formation of human serum amyloid A

Amyloid ◽

10.3109/13506129.2016.1168292 ◽

2016 ◽

Vol 23 (2) ◽

pp. 67-75 ◽

Cited By ~ 11

Author(s):

Hiroka Takase ◽

Masafumi Tanaka ◽

Aki Yamamoto ◽

Shiori Watanabe ◽

Sanae Takahashi ◽

...

Keyword(s):

Human Serum ◽

Serum Amyloid A ◽

Amyloid Fibril ◽

Fibril Formation ◽

Serum Amyloid ◽

Structural Requirements ◽

Amyloid A ◽

Amyloid Fibril Formation

Download Full-text

Influence of C-terminal truncation of murine Serum amyloid A on fibril structure

Scientific Reports ◽

10.1038/s41598-017-06419-1 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 7

Author(s):

Matthies Rennegarbe ◽

Inga Lenter ◽

Angelika Schierhorn ◽

Romy Sawilla ◽

Christian Haupt

Keyword(s):

Serum Amyloid A ◽

Serum Amyloid ◽

Amyloid A ◽

Fibril Structure

Download Full-text

Fibril formation from recombinant human serum amyloid A

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/0925-4439(94)90044-2 ◽

1994 ◽

Vol 1226 (3) ◽

pp. 323-329 ◽

Cited By ~ 46

Author(s):

Toshiyuki Yamada ◽

Barbara Kluve-Beckerman ◽

Juris J. Liepnieks ◽

Merrill D. Benson

Keyword(s):

Human Serum ◽

Serum Amyloid A ◽

Fibril Formation ◽

Serum Amyloid ◽

Amyloid A

Download Full-text

Serum amyloid A sequesters diverse phospholipids and their hydrolytic products, hampering fibril formation and proteolysis in a lipid-dependent manner

Chemical Communications ◽

10.1039/c8cc01424h ◽

2018 ◽

Vol 54 (28) ◽

pp. 3532-3535 ◽

Cited By ~ 7

Author(s):

Shobini Jayaraman ◽

Donald L. Gantz ◽

Christian Haupt ◽

Marcus Fändrich ◽

Olga Gursky

Keyword(s):

Serum Amyloid A ◽

Amyloid Fibril ◽

Fibril Formation ◽

Serum Amyloid ◽

Dependent Manner ◽

Amyloid A ◽

Amyloid Fibril Formation

Serum amyloid A can solubilize diverse phospholipids and their hydrolytic products to form lipoprotein nanoparticles, which hampers amyloid fibril formation.

Download Full-text

Cleavage, down-regulation and aggregation of serum amyloid A

10.1101/811398 ◽

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.

Download Full-text