Revisiting misfolding propensity of serum amyloid A1: Special focus on the signal peptide region

Haines, Morgan S.; Ramirez, Eduardo; Moore, Kendall B. E.; Fortin, Jessica S.

doi:10.1016/j.bbrep.2022.101284

Cited by 4 publications

(4 citation statements)

References 28 publications

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“…On investigating further, we found the signal peptide of APP to be aggregating into amyloids in vitro conditions . Similar to this, signal peptides of serum amyloid A proteins of 16 different species were demonstrated to aggregate, where most of them aggregated at as low as 100 μM concentration . These reports provide direct evidence for the amyloidogenic propensity of signal peptides to convert into a cytotoxic insoluble state in vitro .…”

Section: Discussionsupporting

confidence: 74%

Potential of ADAM 17 Signal Peptide To Form Amyloid Aggregates in Vitro

Bhardwaj,

Giri

2023

ACS Chem. Neurosci.

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ADAM 17, a disintegrin and metalloproteinase 17 belonging to the adamalysin protein family, is a Zn 2+ -dependent type-I transmembrane α-secretase protein. As a major sheddase, ADAM 17 acts as an indispensable regulator of chief cellular events and controls diverse cytokines, adhesion molecules, and growth factors. The signal peptide (residues 1–17) of ADAM 17 targets the protein to the secretory pathway and gets cleaved off afterward. No other function is documented for the ADAM 17 signal peptide (ADAM 17-SP) inside the cells. Here, we have taken a reductionist approach to understand the biophysical properties of ADAM 17-SP. Aiming to understand the possibility of aggregation, we found several aggregation-prone segments in the signal peptide. We performed in vitro experiments to show that the signal peptide forms amyloid-like aggregates in buffered conditions. We also studied its aggregation in the presence of sodium tripolyphosphate and heparin to correlate with the cellular conditions, as these biomolecules are naturally present inside cells. Further, we performed seeding experiments to observe the possibility of ADAM 17-SP aggregate interaction with the Aβ42 peptide. The results suggest that its seeds escalate the aggregation kinetics of the Aβ42 peptide and form heteromeric aggregates with it. We believe this finding could further intensify the aggregation studies on other signal peptides and shed light on the potential role of these segments other than signaling.

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Section: Discussionsupporting

confidence: 74%

Potential of ADAM 17 Signal Peptide To Form Amyloid Aggregates in Vitro

Bhardwaj,

Giri

2023

ACS Chem. Neurosci.

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“…This region was previously deemed an aggregation hotspot and seeding factor of the SAA peptide within humans (Haines et al. 2022 ). In addition, our previous work on the SAA1 human protein indicated that the region 1-25 is highly prone to aggregate (Haines et al.…”

Section: Discussionmentioning

confidence: 93%

“…Upon examination of the human SAA1 peptide sequence, it was observed that the 1-25 aa region exhibited a tendency for aggregation (Haines et al. 2022 ). To expand the investigation to other species, sequences of the SAA1 peptide from eight different species, with a specific focus on the 1-25 aa region, were obtained.…”

Section: Resultsmentioning

confidence: 99%

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Investigation of serum amyloid a within animal species focusing on the 1-25 amino acid region

Horgan,

Moore,

Fortin

2023

Veterinary Quarterly

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AA amyloidosis, characterized by the misfolding of serum amyloid A (SAA) protein, is the most common amyloid protein disorder across multiple species. SAA is a positive-acute phase protein synthesized by the liver in response to inflammation or stress, and it normally associates with high-density lipoprotein at its N-terminus. In this study, we focused on the 1-25 amino acid (aa) region of the complete 104 aa SAA sequence to examine the aggregation propensity of AA amyloid. A library comprising eight peptides from different species was assembled for analysis. To access the aggregation propensity of each peptide region, a bioinformatic study was conducted using the algorithm TANGO. Congo red (CR) binding assays, Thioflavin T (ThT) assays, and transmission electron microscopy (TEM) were utilized to evaluate whether the synthesized peptides formed amyloid-like fibrils. All synthetic SAA 1-25 congeners resulted in amyloid-like fibrils formation (per CR and/or ThT staining and TEM detection) at the exception of the ferret SAA1-25 fragment, which generated plaque-like materials by TEM. Ten residues were preserved among SAA 1-25 congeners resulting in amyloid-like fibrils, i.e. F6, E9, A10, G13, D16, M17, A20, Y21, D23, and M24. Amino acid residues highlighted by this study may have a role in increasing the propensity for amyloid-like fibril formation. This study put an emphasis on region 1-25 in the mechanism of SAA1 misfolding.

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