Structural Basis of Protein Phosphatase 1 Regulation
March 24, Tue 2009
1:00 pm, MRB 100 Conference Room
Dr. Wolfgang Peti
Department of Molecular Pharmacology, Physiology & Biotechnology, Brown University
Signaling cascades direct information transmission and, in turn, function in processes as diverse as memory and muscle movement. These cascades are mediated by a network of highly specific and tightly regulated protein:protein interactions, including those made by serine/threonine kinases and serine/threonine phosphatases. We are achieving an in-depth understanding of signaling networks with a special focus on serine/threonine phosphatase signaling, by using chemical, biochemical, biophysical, structural biology, especially NMR spectroscopy and X-ray crystallography, and in vivo technologies. Our current focus is 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. In this presentation, we will provide the first molecular insight into the interaction of PP1 with multiple essential PP1 regulatory protein, including spinophilin, the most important neuronal PP1 targeting protein that regulates AMPA receptor trafficking among other critical biological functions, as well as other essential targeting proteins and inhibitors.