CURRENT RESEARCH
Wolfgang Peti, PhD
Manning Assitant Professor
Department of Molecular Pharmacology, Physiology & Biotechnology
The focus of the Peti laboratory is the structure, the dynamics and the interaction of proteins using solution state NMR spectroscopy.
Proteins are the main functional building blocks of our body and signaling information, how we sense and react to our environment, is communicated in the cell by phosphorylation of specific residues of these proteins. A vast, integrated network of proteins ensures that only specific proteins are phosphorylated and/or dephosphorylated at certain times to guarantee full function. If this regulation, especially in the brain, is disrupted, it often leads to disease, resulting in dramatically altered behavior, development and interaction. It is my overall scientific aim to translate our understanding of these protein signaling cascades into high resolution 3-dimensional pictures. This will enable us to study the protein:protein interactions that mediate this signaling in detail at atomic resolution. Our technique of choice for these studies is Nuclear Magnetic Resonance (NMR) spectroscopy, which is best known in day-to-day life as magnetic resonance imaging (MRI), its low resolution equivalent. The 3-dimensional models we elucidate using NMR will allow us to not only understand how these proteins mediate and regulate signaling, but also to develop small molecules, most often used as drugs, which modulate the activity these proteins. Therefore, we will be able to either enhance or disrupt such protein:protein interactions, and therefore enhance or disrupt complete signaling pathways, critical for curing diseases. Only by developing these detailed pictures we will be able to influence these pathways individually, ensuring less signaling cross-talk and therefore higher selectivity of drugs with fewer risks.
One current focus is the multiple protein:protein interactions mediated by two proteins, Spinophilin and Neurabin, which function to modulate the shape of dendritic spines in neurons, the primary cells of the brain. Dendritic spines are small, stubby, cellular protrusions of neurons which are critical for the communication between neurons. Moreover, the shape, density and dynamics of dendritic spines are correlated with memory, development and behavior. The primary protein component of dendritic spines responsible for their morphology is actin. Critically for our work, Spinophilin and Neurabin bind and regulate actin. Furthermore, they also interact and regulate protein phosphatase 1 (PP1), an extremely important protein responsible for dephosphorylation of multiple proteins in the body, but especially the brain. Spinophilin and Neurabin, in addition to interaction with actin, also function to target PP1 to its points of action in neurons, which are neurotransmitter-binding membrane receptors. Membrane receptors are the ‘doors’ for neurons, which enable outside signals, usually provided by small chemical substances, neurotransmitters, like glutamine and dopamine, to be communicated to the cell. The phosphorylation and dephosphorylation of these receptors tightly regulate the opening and closing times of these neuronal ‘doors’. The 3-dimensional structures of the interactions of Spinophilin and Neurabin with their actin and PP1 binding partners will provide a detailed understanding of the specificities of these interactions and will allow us to selectively modulate particular signaling cascades for medical benefit.
A second focus is the challenge of the status quo, which says that only proteins with a 3-dimensional structure can fulfill a function. Linus Pauling stated in 1946 “Answers to many basic problems of biology-nature of growth, mechanism of duplication of viruses and genes, action of enzymes, mechanism of physiological activity of drugs, hormones, and vitamins, structure and action of nerve and brain tissue-may lie in knowledge of molecular structure and intermolecular reactions”. However, in recent years it has been shown that also unstructured or partially structured proteins also fulfill essential functions. Usually these proteins fold upon binding to their targeting protein and, in this way, are critical for mediating numerous regulatory events. My laboratory has identified a large number of these intrinsically unstructured protein or protein domains which are, significantly, particularly important in the brain. Our current efforts are focused on identifying and developing methods that will enable us to determine the 3-dimensional structure of these unstructured proteins. This, in turn, will allow us to elucidate the rules that govern their folding upon binding interaction and advance our understanding of this new paradigm of protein:protein interactions.
