When the human genome sequence was unveiled two decades ago, scientists predicted that there were about 20,000 protein-coding genes. To date, researchers have found evidence for more than 18,000 of them. The remainder, as well as modified proteins and those with unknown structures and functions, comprise the "dark proteome." A cover story in Chemical & Engineering News, an independent news outlet of the American Chemical Society, describes how scientists are looking for these hidden proteins.
Using mass spectrometry and other analytical techniques, researchers have found traces of just over 90% of the proteins predicted to exist, writes senior editor Laura Howes. Some of these unknown proteins could play important roles in health and disease, but they might evade detection because they are expressed sporadically, at low levels or only in certain tissues. Alternatively, these proteins could lack features, such as trypsin digestion sites, that allow detection by current techniques. Researchers are developing new approaches — for example, digesting proteins with enzymes other than trypsin to prepare samples for mass spectrometry — but the payoff isn't guaranteed, and there are still other regions of the dark proteome to explore.
One dark region includes "known" proteins that have multiple forms and modifications. Messenger RNA from a single gene can sometimes be spliced together in multiple ways, producing different versions, or "isoforms." Isoforms of a protein can do slightly different things in different parts of the body. Proteins can also be chemically modified in different ways, like adding sugar molecules or methyl groups. Researchers are developing new analytical tools to more sensitively explore this area of the dark proteome. Yet another region includes proteins with unknown structures or functions. Artificial intelligence (AI)-based methods are helping to predict some dark structures, which scientists hope will provide clues to the proteins' functions. Other clues to function can come from gene silencing experiments and AI algorithms that predict protein interaction partners. There could still be areas of the dark proteome that scientists don't even know about, experts say, which will keep researchers intrigued about these mysteries for years to come.
The article is available at https://cenm.ag/darkproteome
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