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New Proteins In New Ways

Well, biology is marching on, even outside the virology that’s on all of our minds. Have a look at this paper, which is looking at the very small proteins I last wrote about here. (Here’s a commentary on this new work as well). What we’re seeing is yet more strong evidence for such species being numerous, important, and (up until recently) missed by many of our molecular biology techniques. We’ve had to rework our thinking about cell biology over the years as the variety of RNA subtypes became clear, and it looks like we’re going to have to do that again around these tiny proteins.

The rules we’ve largely been following for finding proteins in the cell to study include length (because sequences of fewer than 100 amino acids were thought less likely to fold into anything useful), presence of a canonical open reading frame (ORF) with a standard AUG start codon, and demonstration of evolutionary conservation and homology to other proteins. Hah! We appear to be in the process of tossing those out the window. This new work shows (in line with other studies over the last few years) that many so-called “noncoding” RNA sequences are being translated into proteins and that these proteins are in fact functional. This is happening in many cases through noncanonical ORFs, several varieties of them. Careful large scale loss-of-function screens turn these things up, and working backwards shows that we’ve been missing many thousands of functional proteins and many active RNA regions that are apparently important for RNA functions in general, such as via modulating the expression of proteins that we had already annotated by conventional means.

There are some patterns, such as these new proteins being localized with others produced on the same stretches of larger mRNAs, but we’re going to be figuring out these things for quite some time to come. The loss-of-function screens show these small species having noticeable effects on cellular growth and overall gene expression profiles, and you’d have to think that we’re going to start making connections to various disease states as we start to understand more.

I can tell you, I’m having to change my own thinking. Back when the ENCODE consortium came out with their (rather high at the time!) estimates for how much of the genome was actually transcribed, I was more in the skeptics’ camp. But time seems to have been proving those estimates more correct than not. One of the particularly puzzling things (as noted in this new paper) is that we’re seeing proteins that have real functions but do not seem to be evolutionarily conserved. (That was one of the objections back then, that if you can have all those mutations then the so-called protein must not be real). Well, here we are. I wonder if some of this can be explained by the weirdness of disordered proteins? Those sometimes don’t seem to care much about sequence, either, so long as their overall properties are maintained.

As the authors of this new paper say, it shows “a previously unappreciated complexity of the functional mammalian proteome“, and how. We are all going to have to get used to thinking differently about what functional proteins look like, how they’re produced, what they can do, about the relationships between protein regulation and RNA regulation, and more besides. Want an example of how much we don’t know about cell biology? You’ve got another one right here. I suppose the folks talking about modeling the inner workings of the cell in silico will have to tweak their code just a tiny bit. . .


7 comments on “New Proteins In New Ways”

  1. metaphysician says:

    Random non-expert thought- maybe there are a range of biological functions that are both:

    1. Extremely rugged and fault tolerant in their execution

    2. Can be achieved in a wide variety of different ways

    So, you have this giant mass of widely varying and variable proteins which cover these functions. They aren’t evolutionarily conserved because:

    1. Any given mutation has a high chance of leaving a protein that still does the job well enough

    2. Even if the mutation disables the protein, there’s another one that also fulfills the task

    3. Even if most of the proteins are disabled, the function is resilient enough that the result isn’t clinically meaningful

    So, this RNA and these proteins do stuff, but its so filled with low power and overlapping effects that its functionally impossible to see what it does, at least with our current tech.

  2. dearieme says:

    ‘many so-called “noncoding” RNA sequences are being translated into proteins’: are those sequences the sort of thing that people refer to as “junk”?

  3. SomeBiochemist says:

    Asking as part if a proteomics lab:
    How many of these newly discovered small proteins are getting included into uniprot/swissprot data base and how frequently is this updated? I don‘t like the thought that some interesting finding might be in my data, but i can‘t see it, since the protein/peptide is not included in my database..

    1. Derek Lowe says:

      Now that’s a good question – I’m not sure how the databases are equipped to handle these things.

  4. Andre Brandli says:

    Derek, this is indeed an interesting study. Peptides derived from these new proteins are also presented on HLA-I, which suggests that they contribute to the antigen repertoire and modulate immunogenicity. The apparent absence of evolutionary conservation requires in my opinion further investigation. How is the situation in species closely related to human, such as chimpanzees or gorillas? Is there some degree of conservation among mammals? If there is no conservation, there will be no way of studying gene functions in animal models. The functional data provided in the paper are restricted to functions of cells in culture. A more rigorous analysis would require the generation of loss-of-function mutations in mice. A final point, 2/3 of these novel proteins (2342 out of 3455) are encoded upstream of the canonical ORF (Fig. 1A). CRISPR-Cas mediated gene disruption used to study gene function might also interfere with the translation and/or function of the canonical protein on the mRNA. At present, the functional significance of these microproteins are still very questionable.

  5. Aaron says:

    >Want an example of how much we don’t know about cell biology? You’ve got another one right here. I suppose the folks talking about modeling the inner workings of the cell in silico will have to tweak their code just a tiny bit. . .

    once again, I am reminded of the infamous “Can a biologist fix a radio?” paper.

    honestly it’s kind of amazing how far modern medicine has come and we still only sort of know how a human body works

  6. Barry says:

    We’ll have to re-revise the number of “genes” in the human genome.

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