One project in the Peti Lab focuses on the role of the ubiquitous serine/threonine Protein Phosphatase 1 (PP1) that is responsible for ~33% of all de-phosphorylation reactions in the human body. PP1 is a single domain catalytic protein that is exceptionally well conserved, from fungi to human, in both sequence and function. PP1 regulates a large variety of essential cellular processes including cell cycle progression, protein synthesis, muscle contraction, carbohydrate metabolism, transcription and neuronal signaling. However, apo-PP1, while an effective enzyme, entirely lacks substrate specificity. Instead, it depends on a diverse set of regulatory proteins to confer specificity towards distinct substrates.
To achieve the high level of specificity that is required to regulate all of these cellular events, PP1 has evolved diversification through interactions with a large number of regulatory proteins (~200) that form highly specific holoenzymes, rather than using gene duplication and sequence changes. PP1 regulatory proteins include both inhibitory proteins that keep PP1 in an inactive state and targeting proteins that localize PP1 to its point of action and also prime it to dephosphorylate specific substrates. Despite its biological importance, the molecular basis for this ability of regulatory proteins to direct the specificity of PP1 is not understood.
By studying a large and diverse group of PP1 regulatory proteins, we will be able to achieve our long-term goal of predicting the mode of PP1 regulation from the sequence of the PP1 regulatory proteins. Taken together, this work will provide fundamental insights into the regulation of PP1 at the molecular level and will, as a long-term goal, enable us to selectively modulate these particular signaling cascades for medical benefit.