| This work concerns two different modes of auto-regulation in two cell signaling proteins, the protein tyrosine kinase Abl and the Ras activator Sos. The first section contains a proposed mechanism for the regulation of the Abl kinase domain, based on analysis of crystal structures and molecular dynamics simulations. We propose that switching between distinct inactive conformations is an important functional property of the Abl kinase domain, and show how a set of mutations found in patients with chronic myeloid leukemia may inhibit this process. In the second part of this work, I present a crystal structure of Sos that is the first to contain the Sos histone-like fold together with the DH, PH, Rem and Cdc25 domains. Structural analysis suggests that the histone-like fold regulates Sos activity by stabilizing the DH, Rem and Cdc25 domains in the inactive form of Sos. This regulatory function of the histone-like fold may be weakened by several Sos mutations found in patients with the genetic disorder Noonan syndrome. |
