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SOS needs help getting active

The allosteric Ras-binding site (green) of SOS is blocked by its own domains (gray and olive). KURIYAN/ELSEVIER

A Ras activator takes care with its own inhibitory domain to prevent an accidental Ras outbreak, according to structural studies from Holger Sondermann, John Kuriyan (University of California, Berkeley, CA), and colleagues.

Ras turns on MAPK pathways that trigger big changes in cell physiology that lead to cell growth, survival, or differentiation. "Its pathways control so many [extensive] outputs, you really want to avoid false activation," says Sondermann. His work now shows that the necessary care is taken by Ras's nucleotide exchange factor, SOS.

SOS helps Ras expel GDP to make room for GTP, which activates Ras. RasGTP then begins a positive feedback loop—previous studies show that RasGTP binds to an allosteric site on SOS and stimulates its exchange activity. But the new structures, which include a larger piece of SOS than previously crystallized in complex with Ras, show that SOS is normally autoinhibited. Two of SOS's own domains block the allosteric binding site for Ras.

When the two intruding domains are removed, the allosteric SOS site can bind to RasGTP or, with a 10-fold lower affinity, RasGDP. This binding activates exchange activity by increasing the affinity of the SOS catalytic site for Ras. SOS mutants that were unable to accommodate Ras in the allosteric site were also unable to stimulate MAPK pathways downstream of Ras.

What pushes aside the blocking domains in vivo is not known, but it probably ensures that a small blip in RasGTP levels does not turn into full-blown MAPK activation unless conditions warrant it. Growth factor stimulation is known to result in SOS membrane localization and thus activation, possibly by making the allosteric site more accessible to Ras. Phosphorylation by receptor tyrosine kinases might also alter SOS's structure and thus move the blocking domains out of the way.

Reference:

Sondermann, H., et al. 2004. Cell. 119:393–405.[CrossRef][Medline]

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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This Article Full Text (PDF, 589K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Social Bookmarking                            What's this?