The Interdependent Activation of Son-of-Sevenless and Ras
- 1Department of Molecular and Cell Biology, California Institute for Quantitative Biosciences, Howard Hughes Medical Institute, University of California, Berkeley, California 94720
- 2Departments of Molecular and Cell Biology and of Chemistry, California Institute for Quantitative Biosciences, Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Howard Hughes Medical Institute, University of California, Berkeley, California 94720
- Correspondence: kuriyan{at}berkeley.edu
Abstract
The guanine-nucleotide exchange factor (GEF) Son-of-Sevenless (SOS) plays a critical role in metazoan signaling by converting Ras•GDP (guanosine diphosphate) to Ras•GTP (guanosine triphosphate) in response to tyrosine kinase activation. Structural studies have shown that SOS differs from other Ras-specific GEFs in that SOS is itself activated by Ras•GTP binding to an allosteric site, distal to the site of nucleotide exchange. The activation of SOS involves membrane recruitment and conformational changes, triggered by lipid binding, that open the allosteric binding site for Ras•GTP. This is in contrast to other Ras-specific GEFs, which are activated by second messengers that more directly affect the active site. Allosteric Ras•GTP binding stabilizes SOS at the membrane, where it can turn over other Ras molecules processively, leading to an ultrasensitive response that is distinct from that of other Ras-specific GEFs.
