The main focus of this proposal is to understand the function of PP1 in the mammalian brain, where it is known that protein phosphatase-1 (PP1) plays a central role in the integration of postsynaptic neuronal inputs. Hundreds of genes in the human genome encode kinases, yet only a handful of phosphatases have been identified. The mechanisms that control the interplay between these two protein families is at the heart of understanding cellular signaling and communication. One of best studied phosphatases, PP1, is of central importance for numerous cellular processes including cell cycle progression, protein synthesis, transcription and most importantly, neuronal signaling (e.g. memory and depression pathways). PP1 is known to bind at least 65 distinct proteins that are responsible for regulating PP1 activity. One of these proteins is Spinophilin, a PP1 targeting protein that is highly expressed in neurons. Spinophilin targets PP1 to neuronal substrates, which affords rapid response to fluctuating concentrations of neurotransmitters and secondary messengers. The structural and dynamical interactions between PP1 and its targeting proteins, like Spinophilin, are poorly understood. The NMR-based studies proposed here, will allow us to examine the structural basis of Spinophilin:PP1 regulation. The results of this study will add greatly to our understanding of neuronal signaling and will add insights into how neurological disorders, like Parkinson's Disease, operate. ? ? ?
| Kelker, Matthew S; Page, Rebecca; Peti, Wolfgang (2009) Crystal structures of protein phosphatase-1 bound to nodularin-R and tautomycin: a novel scaffold for structure-based drug design of serine/threonine phosphatase inhibitors. J Mol Biol 385:11-21 |
| Kelker, Matthew S; Dancheck, Barbara; Ju, Tingting et al. (2007) Structural basis for spinophilin-neurabin receptor interaction. Biochemistry 46:2333-44 |
