Interview with a protein: Sos1

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One of the roles of Sos1 in cell signaling. Sos1, a protein usually found in the cytoplasm, activates the Ras protein at the cell membrane. To get to Ras, Sos1 binds to an SH3 domain in the Grb2 protein, which can bring Sos1 to the cell membrane in response to a signal. At the membrane, Sos1 is activated by Ras in a feedback loop. Illustration adapted from work by Lore Leighton.

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An artist’s rendering of the domains in a Sos1 protein. Very similar to how it appeared in Sondermann et al., 2005.

The Sos1 protein participates in several eukaryotic cell signaling pathways, including insulin, FGF, and EGF signaling. These pathways lead to cell growth and survival, cytoskeletal organization, or changes in transcription. Mice lacking Sos1 die as embryos. A serious human genetic disorder called Noonan syndrome has recently been linked to mutations in Sos1.

My lab mates and I here at the University of California, Berkeley, study how proper Sos1 function depends on the different domains parts of Sos1. In a very rare journalistic opportunity, I was able to interview a few of the Sos1 domains. I wanted to learn more about their jobs.

Kuchment: Cdc25, could I ask you a few questions about your work?

Cdc25: Sure, but make it quick.  

Kuchment: So what do you do in Sos1?

Cdc25: I catalyze the exchange of GDP for GTP in molecules of Ras. That way, very important signals can continue to be sent to various parts of the cell. Actually, Rem and I make a really good team, and when we have an allosteric Ras bound we really get cracking. If it wasn’t for those DH and PH domains blocking that binding site all the time, we’d get so much more work done!

Kuchment: Say, is that the PXXP region over there?

Cdc25: That’s right. That guy is a complete slacker. He’s out there catching passing SH3 domains all day. I keep telling him to take control of his life. He’s always like, ‘Dude, you gotta hang loose, go with the flow.’ Well, that’s why you don’t see him catalyzing important reactions. Anyway, I can’t stand around talking all day. I need to focus on getting in shape for binding Ras.

Kuchment: DH domain, what do you do?

DH domain: Well...most of the time I’m just stuck to the side of the Rem domain, with my buddy PH. To tell you the truth, sometimes I feel like I’m missing out on life. My cousin in Dbl (I was named Dbl Homology – DH for short – after him) catalyzes GDP to GTP exchange... It would be so exciting if I could do that!

PH: Did somebody say lipids? I could really use a lipid head group right now, like maybe a phosphoinositol-4,5-bisphosphate, you know?  I just love the way the negatively charged phosphates fit with my positively charged arginines and lysines. Hey guys, let’s go hang out by the cell membrane! Any takers?

Histone: I’m up for it.

Kuchment: Histone domain, what do you do?

Histone: Well, I also like negatively charged lipid head groups. And I work pretty closely with the helical linker between the PH and Rem domains, one arginine in particular.  

Kuchment: Could you be more specific?

Histone: Sorry, I’m not at liberty to say more. Those results have not been published.

Kuchment: Have you heard the news about Noonan syndrome being linked to mutations in Sos1?

Histone: Yes. Very disturbing. I am quite attached to that arginine in the helical linker. If it was mutated to glycine, it would really disrupt my work.   

As you can see, there is much more to this story that is not revealed here. I will continue to strive to get the whole story on the lives of cell signaling protein domains.   

References:

1. A. Roberts, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nature Genetics. Advance Online Publication (December 2006)

2. M. Tartaglia, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nature Genetics. Advance Online Publication ( December 2006)

3. Sondermann, H., Soisson, S.M., Bar-Sagi, D. & Kuriyan, J. Computational docking and solution x-ray scattering predict a membrane-interacting role for the histone domain of the Ras activator Son of Sevenless. Proc. Natl. Acad. Sci. USA 102 , 16632-16637 (2005).

4. Freedman, T. S., Sondermann, H., Friedland, G., Kortemme, T., Bar-Sagi, D., Marqusee, S., & Kuriyan, J. A Ras-induced conformational switch in the Ras activator Son of sevenless. Proc. Natl. Acad. Sci. USA 103 , 16692-16697 (2006).