Abstract
Macromolecular crowding has been shown to have an exacerbating effect on the aggregation propensity of amyloidogenic proteins; while having an inhibitory effect on the non-amyloidogenic proteins. However, the results concerning aggregation propensity of non-amyloidogenic proteins have not been convincing due to the contrasting effect on holo-LA, which despite being a non-amyloidogenic protein was observed to aggregate under crowded conditions. In the present study, we have extensively characterized the crowding-induced holo-LA aggregates and investigated the possible mechanism responsible for the aggregation process. We discovered that macromolecular crowding reduces the calcium binding affinity of holo-LA resulting in the formation of apo-LA (the calcium-depleted form of holo-LA) leading to aggregate formation. Another finding is that calcium acts as a chaperone capable of inhibiting and dissociating crowding-induced holo-LA aggregates. The study has a direct implication to Alzheimer Disease as the results invoke a new mechanism to prevent Aβ fibrillation.
Highlights
The primary sequence of a globular protein is important in making the unfolded proteins en-route to its native, functional three-dimensional structure via intramolecular interactions [1, 2]
We further propose that increasing the expression of calcium-binding proteins might help to reduce Alzheimer Disease (AD) pathogenesis by offsetting the aggregation of Ab
Tagg and Ti are observed to decrease in a crowder concentration dependent manner suggesting that the native state of the protein has been destabilized by Ficoll 70 subsequently resulting in aggregation initiation from lower temperatures
Summary
The primary sequence of a globular protein is important in making the unfolded proteins en-route to its native, functional three-dimensional structure via intramolecular interactions [1, 2]. The cells interior is known to be densely populated due to the presence of soluble and insoluble macromolecules (proteins, nucleic acids, ribosomes and carbohydrates etc) [16, 18], which together make the intracellular environment ‘‘crowded’’ or ‘‘volume-occupied’’ rather than ‘‘concentrated’’ [18, 19, 20]. Results in altered biological processes including protein folding and aggregation as compared to those under dilute buffers [18]. Until recently, this difference was mainly accounted by the excluded volume effect [21, 22]. A great deal of recent work [23, 24] shows that in addition to excluded volume effect, soft interactions play an important role in determining macromolecular properties
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