What Percentage Of Protein Isoforms Have Different Functions?

Question

[terdon]

I am looking for studies on how many protein isoforms have different functions, preferably in human. We know that a great many, if not most, of human genes are alternatively spliced and that many produce different protein isoforms. Has anyone looked at how many of these isoforms have different cellular functions? If someone could point me to a published paper, that would be great.

If no such study has been made, can anyone recommend a database from which this information could be extracted? GeneOntology is gene based so the information cannot be found there. Genes will be annotated to specific terms, not their protein isoforms. Also, I would need to be able to do this in a high throughput manner, I am not interested in specific proteins but in what percentage of all isoforms have different functions.

Ideally, I would like to be able to extract, for every human gene, the list of the different protein isoforms it encodes and whether their functions differ, or at least what those functions are.

[Larry_Parnell]

This is an interesting endeavor. One of the first things to be considered, in my opinion, is the definition of function, or how nuanced you need to be to properly, completely describe that protein's function. Most isoforms will likely have the same basic function but differ in something like sub-cellular localization or loss of a regulatory sub-domain. In other words, alternate splicing will lead to different protein isoforms with slightly different function in light of the primary function of the protein.

[terdon]

Yup, exactly, that's what I want to analyze. My first step though is to see how often different isoforms are annotated to different functions and I can't figure out where to get that information because too many of the high-troughput functional assays are gene based.

Answer 1

[Biojl]

You might find the information you seek for a few well characterized genes but in general there's still a lot of genes without a well-established function. For most organisms, except perhaps human and mouse, there is not even a good (or any) description of different isoforms.

I would be very interested in such data but right now I think is science fiction since establish the function of only one gene (and isoforms) might take years of experiments.

UPDATE The only thing you could do in well annotated species, like human or mouse, is studying the expression of different ratios of isoforms in different conditions/species. Such information can be extracted from RNAseq experiments with Flux capacitor http://flux.sammeth.net/capacitor.html

Answer 2

[Niallhaslam]

I think the simple answer is that this hasn't been done yet for the whole proteome (to the best of my knowledge). There have been a few attempts for different tissue types, looking at which exons are expressed in different tissues.

There were a couple of articles highlighted in Nature Reviews Genetics last year about this topic.

If you just want the list of isoforms of each protein then UniProt will have that information. Unfortunately I don't think the information about the function of alternative transcripts is all that well characterised. At best I'd imagine you'd get tissue specificity but even then its not complete.

[terdon]

Thanks, I'll have a look at the papers. As for Uniprot, you're exactly right, they have the number of isoforms and in some cases different functions but not always and not organized in any meaningful way.

Answer 3

[Mary]

Huh. I've never seen that addressed specifically. An interesting challenge.

But I guess I'd also ask: which protein isoforms don't change function? And why bother making different ones then?

Another issue would be alterations in non-coding regions like 3' UTRs. There seemed to be tissue-specific reasons for some that I've seen, and that might not affect the protein sequence but might affect function still. Or maybe not. So those could be splicing variants that don't change function.

[terdon]

Well, changes in UTRs do not result in different protein isoforrms, so that doesn't really enter into it. As for which and why, it depends in what you consider different functions. The different isoforms could just have a different pH sensitivity but catalyze the same reaction, or they could have different ligands yet both be receptors and both activate the same pathway. In both cases, the essential function is the same. Though they are not, strictly speaking, isoforms since they come from different gene arrangements, antibodies while different, all have the same cellular function.

[Mary]

Oh, well, then it does get to your definition of function then. I'd think that catalysis at a different pH would count as a different function, because that could represent a different cellular condition. I'd count differential regulation in a tissue-specific manner by some feature of the UTR to be a function of a different spliced transcript. So the first problem would be for you to define what you consider a different function, eliminating all those you wouldn't count.