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Impact Of The Presence Of Protein Aggregates

1822 words - 8 pages

In the last decade, protein aggregation, protein aggregation has moved beyond being a mostly ignored area of protein chemistry to become a key topic in biomedicine and biotechnology [1]. Several are the reasons for the increasing interest on the molecular mechanisms underlying protein aggregation. First, the presence of protein aggregates in tissues is hallmark of more than 40 different human disorders, from neurodegenerative diseases such as Alzheimer’s, Parkinson’s, or the transmissible spongiform encephalopathies to nonneurodegenerative systemic and localized amyloidosis, as senile systemic amyloidosis, type 2 diabetes, or even some types of cancer. A second reason is found in the large ...view middle of the document...

In addition, even when a protein-based biopharmaceutical is produced and purified in a soluble form it still at risk of aggregation, during late research stages, manufacturing, storage or administration. In fact, therapeutic proteins are typically stored and administered at significantly high concentrations, at which they can easily aggregate. Aggregation would impact the effectiveness of the drug, since less active species will remain available in solution to interact with their molecular targets. More importantly, often this situation leads to an immunogenic response causing rejection of the aggregated product in patients.

Why protein aggregation is so prevalent?
Protein aggregation results from the establishment of wrong inter-molecular contacts between protein chains. These contacts are often regular, rendering assemblies that result to be as energetically favourable or more energetically favourable than the native state of the protein. Different types of aggregates may exist: (i) soluble aggregates, which are invisible particles that cannot be eliminated from solution by filtration, (ii) insoluble aggregates are often visible and can be removed by filtration. This last type of aggregates has attracted most of the attention in the last years, since in many cases their formation inside or outside the cell affects cell fitness and ultimately leads to disease. Irrespective of the nature of the proteins involved in these disorders, the aggregates usually adopt the form of amyloid fibrils, all sharing a common cross-β sheet structure in which the main chain dominates the protein structure, forming β-strands that are oriented perpendicularly to the axis of the fibril and stabilized by hydrogen bonds (Fernandez-Busquets et al., 2008. When observed under X-rays, aligned amyloid fibrils display two common and characteristic scattering diffraction signals, a meridional reflection at 4.7–4.8 Å and equatorial reflection at 10–11 Å corresponding to the inter-strand and stacking distances in β-sheets, respectively. Amyloid fibrils are usually 10 nm in diameter and they are formed by several protofibrils twisted around each another. Protofibrils are the most toxic species to the cell. Contrary to what was generally assumed, the adoption of cytotoxic amyloid-like conformations is not restricted to disease-linked proteins and seems to constitute a generic property of polypeptide chains. In fact, despite not all insoluble aggregates correspond to amyloid structures the large majority are enriched in β-sheet secondary conformations relative to the native state.
Aggregation is prevalent in proteins likely because the non-covalent contacts that stabilize native structures resemble those leading to the formation of aggregates. Indeed, a majority of proteins contain at least one and often several aggregation-promoting sequences in many cases buried in the hydrophobic core of the native structure. Therefore, productive protein folding and aggregation are...

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