Abstract
Proteinopathies are diseases caused by factors that affect proteoform conformation. As such, a prevalent hypothesis is that the misincorporation of noncanonical amino acids into a proteoform results in detrimental structures. However, this hypothesis is missing proteomic evidence, specifically the detection of a noncanonical amino acid in a peptide sequence. This review aims to outline the current state of technology that can be used to investigate mistranslations and misincorporations whilst framing the pursuit as Misincorporation Proteomics (MiP). The current availability of technologies explored herein is mass spectrometry, sample enrichment/preparation, data analysis techniques, and the hyphenation of approaches. While many of these technologies show potential, our review reveals a need for further development and refinement of approaches is still required.
Highlights
The “central dogma” of molecular biology suggests that the translation of one gene results in the expression of a single protein [1]
Within the isolation window for precursor transmission accumulation and fragmentation (1.4 Da in an orbitrap (± 0.7 Da)) there is a potential that the fragmented species may be derived from more than one single ion population given the likelihood of similar m/z ion species being found within the isolation window selected for fragmentation
The ways to overcome the lack of theoretical data available to predict the effect of nonprotein amino acids (NPAAs) incorporations on produced mass spectrometric (MS)/MS spectra is through the use of tools that enable the prediction of retention times and elution windows for these unknown species
Summary
The “central dogma” of molecular biology suggests that the translation of one gene results in the expression of a single protein [1]. Translated proteins are known to exist as multiple biological variants or proteoforms [2] These proteoforms are the result of modifications to the polypeptide chain, including the addition, subtraction, or alteration of chemical groups. An incorrect amino acid may be inserted into the growing peptide chain, resulting in a modification in the final proteoform Such errors generate new, non-native proteoforms that have the potential to cause harm to the cell [7,8]. Other issues may include replacement of amino acid residues that are essential sites for activity or post-translational modifications (PTM) in that proteoform Such alterations to the amino acid sequence can hinder a cells ability to operate, as the proteoforms may be nonfunctional, aggregate, or even acquire a toxic gain of function. This may explain why diseases associated with NPAAs tend to be neurological in nature, and why it is of growing importance to investigate misincorporation and its consequences
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
