You may have heard that there are roughly 20,000 genes in the human genome. One might assume that, since genes encode proteins, there can be no more than 20,000 different proteins in any given cell. However, this is far from the case. In the process of transcribing the information in a gene and later translating into a protein, numerous biological processes can result in modifications to the final protein:
All this rearranging and modification explodes the number of possible “proteoforms” that could theoretically be produced in a human cell from 20,000 to millions (Aebersold et al 2018).
The modifications that make up proteoforms can drive biologically interesting changes to protein function. Indeed, the precise mix of proteoforms in a cell can have great impacts on cell processes, organ function, and total body system function. Thus, knowing more about the proteoforms present in healthy and diseased cells may give scientists great insights into how cells and tissues operate. Unfortunately, most proteomics technologies used today cannot distinguish proteoforms, can only see a small fraction of them, or do not have the resolution to capture multiple modifications and their precise composition within a sample.
There are many unknowns when it comes to the world of proteoforms. Scientists have made theoretical predictions about the number of proteoforms that could possibly exist, but it is not at all clear what fraction of these proteoforms are actually made, how they might be distributed across cells, and what functional consequences they have.
Nonetheless, we do know that some protein modifications are highly consequential. For example, the addition of methyl groups to proteins that scaffold DNA can turn off genes that would otherwise suppress cancer development and similar modifications altering gene expression are associated with various cancer outcomes (Nebbioso et al 2018). With the ability to identify specific proteoforms at the single-molecule level in cells and tissues, scientists can more confidently associate proteoforms with various states of health and disease. Such research may lead to better biomarkers that more accurately indicate when a person has a particular disease or the identification of specific proteoforms that may make better targets for novel drugs.
At Nautilus, we’re developing a proteomics platform that is designed to make it easier to identify proteoforms with increased precision.
By getting a more in-depth view of the proteoforms that exist across samples, we’ll take the first step toward understanding how these proteoforms impact health and disease. Once scientists observe differences in proteoform abundance across samples, they can investigate whether those differences are functionally significant. The Nautilus Proteome Analysis Platform aims to bring us a long way toward accomplishing these goals.
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