Protein phosphorylation is one of the most important mechanisms in the eukaryotic cell. To fully understand this mechanism at the molecular level requires not only an understanding of the molecular features of the catalysts, the protein kinases and protein phosphatases, but also an understanding of their regulation and where they are located within the cell. This complex and dynamic network of interactions is mediated by a variety of protein: protein interactions that determine not only whether a protein kinase is active but also where it resides in the cell. This Program Project focus on two of the most important protein kinases, cAMP- dependent protein-kinase (PKA) and protein kinase C (PKC). Specifically, we shall characterize anchoring mechanisms that localize these enzymes to particular compartments within the cell. Our goals are to understand these processes at the cellular biochemical structure levels. To accomplish these goals we have women together a highly interdisciplinary program. Project 1 (S. Taylor) focuses on PKA and its interactions with a novel set of dual specific A Kinase Anchoring Proteins that interact with both RI and RII subunits of PKA and target to mitochondria and ER. Project 2 (J. Scott) deals with gravin, a newly discovered AKAP associated with myosthenias gravis that interacts with both PKC and PKA. Project 3 (A. Newton) focuses on PKC and its specific mechanisms of interaction with membranes and gravin. Project 4 (P. Jennings) is focused on the structural characterization of the anchoring domains and motifs and their dynamic interactions with both PKA and PKC. Our goals are to understand at the molecular level the detailed anchoring and docking motifs associated with PKA and PKC focusing initially on the small domains and motifs but eventually understanding these motifs within the context of the full length anchoring proteins. Our final goal is to understand the physiological basis for anchoring within the cell and the functional importance of anchoring. Four projects are build around three scientific cores. These cores in NMR (P. Jennings), X-ray crystallography (N. Xuong) and Imaging/Electron Microscopy (M. Ellisman/S. Adams), reflect the diversity of our program and emphasize our fundamental conviction that one needs to understand not only the molecular features of the proteins that comprise the anchoring network but also how these proteins function in living cells. The cores provide state-of-the-art technology in these three areas and are designed so the projects as they evolve can move freely between the cores.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Special Emphasis Panel (ZDK1 (M2))
Program Officer
Haft, Carol R
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University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
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Flippo, Kyle H; Gnanasekaran, Aswini; Perkins, Guy A et al. (2018) AKAP1 Protects from Cerebral Ischemic Stroke by Inhibiting Drp1-Dependent Mitochondrial Fission. J Neurosci 38:8233-8242
Sengupta, Soham; Nechushtai, Rachel; Jennings, Patricia A et al. (2018) Phylogenetic analysis of the CDGSH iron-sulfur binding domain reveals its ancient origin. Sci Rep 8:4840
Haushalter, Kristofer J; Casteel, Darren E; Raffeiner, Andrea et al. (2018) Phosphorylation of protein kinase A (PKA) regulatory subunit RI? by protein kinase G (PKG) primes PKA for catalytic activity in cells. J Biol Chem 293:4411-4421
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Nystoriak, Matthew A; Nieves-CintrĂ³n, Madeline; Patriarchi, Tommaso et al. (2017) Ser1928 phosphorylation by PKA stimulates the L-type Ca2+ channel CaV1.2 and vasoconstriction during acute hyperglycemia and diabetes. Sci Signal 10:
Ilouz, Ronit; Lev-Ram, Varda; Bushong, Eric A et al. (2017) Isoform-specific subcellular localization and function of protein kinase A identified by mosaic imaging of mouse brain. Elife 6:
Nygren, Patrick J; Mehta, Sohum; Schweppe, Devin K et al. (2017) Intrinsic disorder within AKAP79 fine-tunes anchored phosphatase activity toward substrates and drug sensitivity. Elife 6:
Aggarwal-Howarth, Stacey; Scott, John D (2017) Pseudoscaffolds and anchoring proteins: the difference is in the details. Biochem Soc Trans 45:371-379

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