Methodological approaches and insights on protein aggregation in biological systems

ABSTRACT

Introduction: The proper folding of native proteins is critical and dynamic, but inherently unstable. Therefore, proteins eventually end up adopting misfolded conformations which compromise their function and may even trigger aggregation. Risk factors for neurodegenerative, metabolic and heart diseases compromise cellular protein quality-control systems, promoting protein aggregation. Multiple protein post-translational modifications dynamically regulate protein aggregation and disaggregation in a very complex, intricate and delicate balance.

Areas covered: Herein, we overview the more promising techniques and approaches for the elucidation of the biological implications of protein aggregation. The particular insights provided by different techniques were discriminated and several examples of post-translational modifications together with their targets were pooled and critically discussed, representing promising future therapeutic targets.

Expert commentary: In the years to come, differences between physiological and pathological protein aggregation will certainly become easier to determine. Techniques such as hydrogen/deuterium exchange, circular dichroism spectroscopy and novel mass spectrometry-based approaches are being optimized and are expected to introduce inhibitors of protein aggregation into the clinic. However, protein aggregation is not an isolated phenomenon, but rather influenced by multiple cellular components which complete knowledge is still far.

KEYWORDS:

• Aggregation
• proteins
• post-translational modifications
• proteomics
• misfolding
• mass-spectrometry

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Additional information

Funding

The authors would like to thank the Portuguese Foundation for Science and Technology (FCT), European Union, QREN, FEDER and COMPETE for funding RV (IF/00286/2015), the iBiMED, UnIC, QOPNA research units (project UID/BIM/04501/2013, UID/IC/00051/2013, PEst-C/QUI/UI0062/2013) and COST action BM1305.