Dataset Information

Cleavage, Downregulation, and Aggregation of Serum Amyloid A.

ABSTRACT: Various diseases cause overexpression of the serum amyloid A (SAA) protein, which in some cases, but not in all cases, leads to amyloidosis as a secondary disease. Response to the overexpression involves dissociation of the SAA hexamer and subsequent cleavage of the released monomers, most commonly yielding fragments SAA_1-76 of the full-sized SAA_1-104. We report results from molecular dynamic simulations that probe the role of this cleavage for downregulating the activity and 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, SAA_1-76 can switch between two distinct configurations. The first kind is easy to proteolyse (allowing a fast reduction of the SAA concentration) but prone to aggregation, whereas 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 increases the risk of amyloid formation, the ensemble shifts toward the more protected form. We speculate that SAA amyloidosis is a failure of this switching mechanism leading to accumulation of the aggregation-prone species and subsequent amyloid formation.

SUBMITTER: Wang W

PROVIDER: S-EPMC7346682 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cleavage, Downregulation, and Aggregation of Serum Amyloid A.

Wang Wenhua W Khatua Prabir P Hansmann Ulrich H E UHE

The journal of physical chemistry. B 20200130 6

Various diseases cause overexpression of the serum amyloid A (SAA) protein, which in some cases, but not in all cases, leads to amyloidosis as a secondary disease. Response to the overexpression involves dissociation of the SAA hexamer and subsequent cleavage of the released monomers, most commonly yielding fragments SAA<sub>1-76</sub> of the full-sized SAA<sub>1-104</sub>. We report results from molecular dynamic simulations that probe the role of this cleavage for downregulating the activity a ...[more]

PMID: 31955564

Similar Datasets

Project description:Aging is the most important risk factor for neurodegenerative diseases associated with pathological protein aggregation such as Alzheimer's disease. Although aging is an important player, it remains unknown which molecular changes are relevant for disease initiation. Recently, it has become apparent that widespread protein aggregation is a common feature of aging. Indeed, several studies demonstrate that 100s of proteins become highly insoluble with age, in the absence of obvious disease processes. Yet it remains unclear how these misfolded proteins aggregating with age affect neurodegenerative diseases. Importantly, several of these aggregation-prone proteins are found as minor components in disease-associated hallmark aggregates such as amyloid-? plaques or neurofibrillary tangles. This co-localization raises the possibility that age-dependent protein aggregation directly contributes to pathological aggregation. Here, we show for the first time that highly insoluble proteins from aged Caenorhabditis elegans or aged mouse brains, but not from young individuals, can initiate amyloid-? aggregation in vitro. We tested the seeding potential at four different ages across the adult lifespan of C. elegans. Significantly, protein aggregates formed during the early stages of aging did not act as seeds for amyloid-? aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-? aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-? plaques and neurofibrillary tangles such as 14-3-3, Ubiquitin-like modifier-activating enzyme 1 and Lamin A/C, highlighting these as strong candidates for cross-seeding. Overall, we demonstrate that widespread protein misfolding and aggregation with age could be critical for the initiation of pathogenesis, and thus should be targeted by therapeutic strategies to alleviate neurodegenerative diseases.

Dataset Information

Cleavage, Downregulation, and Aggregation of Serum Amyloid A.

Publications

Cleavage, Downregulation, and Aggregation of Serum Amyloid A.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets