All organisms have evolved mechanisms to ensure the proper folding and localization of proteins in the face of a variety of stresses that would otherwise kill them. In bacteria, such as Escherichia coli, as well as higher eukaryotes, specialized regulatory systems act to monitor the integrity of cellular proteins. Specifically, both the periplasmic stress response in E. coli and the unfolded protein response in eukaryotic cells employ a transmembrane kinase that senses and transduces a signal within the endoplasmic reticulum (ER) or periplasm, respectively. This signal is then relayed to transcriptional regulators which results in an upregulation of appropriately localized protein folding and trafficking factors that can act to combat the inciting stress. The Cpx-induced stress response of Escherichia coli combats extracytoplasmic toxicities such as the formation of misfolded protein aggregates through a two-component signal transduction system comprised of a kinase (CpxA) and a transcriptional response regulator (CpxR). The periplasmic protein, CpxP, is the only identified negative regulator of the Cpx stress response and presumptively plays an important role in ensuring that this response is properly modulated. While it is clear that CpxP function requires a functional periplasmic CpxA sensing domain, relatively little is known about how CpxP normally functions in the cell. The purpose of this proposed study is to use both biochemical and genetic analysis to dissect CpxP function and understand how its activity is coordinated with the Cpx two-component system to alleviate envelope-associated stress and ensure appropriate activation of the Cpx response. The proposed study will illuminate the way in which the cell adapts to stave off the effects of the presence of toxic protein aggregates. Such aggregates appear to be central to the pathogenesis of several human diseases including alpha-1 antitrypsin deficiency and Huntington's disease. ? ?
| Isaac, Daniel D; Pinkner, Jerome S; Hultgren, Scott J et al. (2005) The extracytoplasmic adaptor protein CpxP is degraded with substrate by DegP. Proc Natl Acad Sci U S A 102:17775-9 |
