The eukaryotic cell: Preadapted for multicellular existence

First, a review.

We’re looking at two different eukaryotic proteins: beta catenin and alpha importin. Beta catenin plays two different crucial roles in metazoan life: 1) It is a key component of the adherens junction which connects cells together and 2) it is involved in the transcription of genes that play an important role in the development of the embryo and the maintenance of organs. This is a neat example of one protein playing two important roles in metazoan life. A simplified figure is shown below, where the beta catenin is represented by the pink circle:

Next are the alpha importins. They transport proteins into the nucleus through the nuclear pore complex. The figure below shows the basic mechanism involved:

The alpha importin is shown in blue. It recognizes and binds the nuclear localization signal (NLS) on a protein that is destined for the nucleus (in the above figure, it is the experimentally designed radioactive protein) and then binds with another protein, beta importin, to be transported into the nucleus.

It is my hypothesis that the alpha importins imposed a form of guidance to evolution by front-loading the eventual emergence of the beta catenins which would, in turn, facilitate the evolution of metazoa. The first line of support for this hypothesis would be to show a homologous relationship between these two different proteins (and as far as I have been able to tell, no one has seriously proposed this). So allow me to make that case.

I began to suspect a homologous relationship between the alpha importins and beta catenin from sequence comparison between a Volvox protein that I previous scored as a beta catenin-like protein and human beta catenin. Put simply, when I probed various protozoan genomes with the Volvox sequence, I found three matches that turned out to be alpha importins.

So I decided to BLAST human alpha importin sequence against human beta catenin sequence. The two proteins share 96/421 (22%) positions with the same amino acid, 170/421 (40%) positions with a biochemically similar amino acid, with an E value of 2e-11 (recall that E values less than 1e-4 are considered homologous).

Added to these sequence data is the fact that the alpha importins and beta catenins have a strikingly similar structure.

Now let’s make it even more interesting by considering the functional overlaps between the two proteins:

1. Both proteins proteins have the ability to transport across the nuclear pore complex.

2. Both proteins have the ability to bind to multiple partners. Alpha importins can bind to any protein that contains a NLS and beta catenins bind to over 20 different proteins.

3. It gets much more interesting. While beta catenin transports into the nucleus, it doesn’t have a NLS signal and enters without the help of alpha importin:

Beta-catenin is imported into the nucleus by binding directly to the nuclear pore machinery, similar to importin-beta/beta-karyopherin or other importin-beta-like import factors, such as transportin. These findings provide an explanation for how beta-catenin localizes to the nucleus without an NLS and independently of its interaction with TCF/LEF-1. This is a new and unusual mechanism for the nuclear import of a signal transduction protein. – Fagotto F, Glück U, Gumbiner BM. 1998. Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of beta-catenin. Curr Biol. 8(4):181-90.

4. Like beta catenin, alpha importins can pass through the nuclear pore complex without assistance (in other words, the beta importin partner is not needed):

These results indicate that importin alpha alone can enter the nucleus via a novel pathway in an importin beta- and Ran-independent manner. Furthermore, this process is evolutionarily conserved as similar results were obtained in Saccharomyces cerevisiae. – Miyamoto Y, Hieda M, Harreman MT, Fukumoto M, Saiwaki T, Hodel AE, Corbett AH, Yoneda Y. 2002. Importin alpha can migrate into the nucleus in an importin beta- and Ran-independent manner. EMBO J. 21(21):5833-42.

5. Best of all is the fact that beta catenins can function as an importin!

Nuclear accumulation of beta-catenin plays an important role in the Wnt signaling pathway. In the nucleus, beta-catenin acts as a transcriptional co-activator for TCF/LEF family of transcription factors. It has been shown that lef-1 contains a typical basic type nuclear localization signal (NLS) and is transported into the nucleus by the conventional import pathway. In this study, we found that a mutant lef-1 lacking the classical NLS accumulated in the nucleus of living cells, when beta-catenin was co-expressed. In addition, in a cell-free import assay, lef-1 migrated into the nucleus in the presence of beta-catenin alone without any other soluble factors. In contrast, another mutant lef-1 lacking the beta-catenin binding domain failed to migrate into the nucleus, even in the presence of beta-catenin. These findings indicate that beta-catenin alone can mediate the nuclear import of lef-1 through the direct binding. Collectively, we propose that there are two distinct pathways for the nuclear import of lef-1: importin alpha/beta-mediated and beta-catenin-mediated one, which provides a novel paradigm for Wnt signaling pathway. – Asally M, Yoneda Y. 2005. Beta-catenin can act as a nuclear import receptor for its partner transcription factor, lymphocyte enhancer factor-1 (lef-1). Exp Cell Res. 308(2):357-63.

So when it comes to the transcription factor lef-1, beta catenin can substitute for alpha importin.

Considering all the structural, sequence, and functional similarities, I think we’re on pretty solid ground in proposing a homologous relationship between the alpha importins and beta catenins. And given that alpha importins are essentially universal among eukaryotes, playing the key eukaryotic role of transporting proteins into the nucleus, it is likely that the alpha importins functioned to nudge the beta catenins into existence. In other words, we can view this core aspect of the eukaryotic cell design as a preadaptation for multicellularity, as if the eukaryotic cell was meant to facilitate the emergence of complex, multicellular existence.

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