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case western reserve university

BIOCHEMISTRY
 
 

Dr. Focco van den Akker

Assistant Professor

Pub Med:

Dr. Focco van den Akker

Multi-facetted structural approach to understanding the molecular signal transduction events of membrane receptors important for blood pressure regulation and bone growth, and other fascinating enzymes

A majority of today's medicines act via membrane bound receptors. These receptors are the communication portals for cells with mostly signals going into the cell but sometimes also signaling from the inside-out. Our lab is mainly focusing on the natriuretic peptide receptors and related receptors which are wonderful complex signal transduction systems to tackle scientifically. These receptors are guanylyl cyclase receptors involved in blood pressure regulation and bone growth and their activation leads to the production of the intracellular second messenger cGMP. Deciphering the molecular signaling intricacies for these receptors is our paramount focus using a battery of approaches such as protein crystallography, cell biology, biochemical, biophysical, and computational ligand design techniques. Such receptor intricacies include ligand binding, transmembrane helix movement(s), de-phosphorylation/desensitization, ATP binding, high-low affinity state switches, kinase-homology domain regulation, and receptor activation and cGMP production. All of these steps are structurally not well understood making these receptors ideal candidates for a concerted multi-disciplinary approach to gain mechanistic insights. We have previously determined the crystal structure of the ligand binding domain of the atrial natriuretic peptide receptor revealing many unexpected discoveries such as its structural similarity with periplasmic binding proteins, possible dual allosteric regulation, the hormone binding site, and dimer interfaces. Our current projects range from relatively straight forward experiments such as site-directed mutagenesis and activity assays to probe specific questions, to biochemically characterizing and crystallizing the remaining individual domains, to our most ambitious long term goals of crystallizing the entire receptor and discovering new pharmaceutically interesting effectors based on our structural investigations.

Selected References

  • Padayatti, P.S., Pattanaik, P., Ma, X., van den Akker, F. Structural insights into the regulation and the activation mechanism of guanylyl cyclases (2004). Pharm. Therapeutics. In Press.

  • Bartels, C.F., Bukulmez, H., Padayatti, P., Rhee, D.K., Van Ravenswaaij-Arts, C., Pauli, R.M., Mundlos, S., Chitayat, D., Shih, L.Y., Al-Gazali, L.I., Kant, S., Cole, T., Morton, J., Cormier-Daire, V., Faivre, L., Lees, M., Kirk, J., Mortier, G.R., Leroy, J., Zabel, B., Kim, C.A., Crow, Y., Braverman, N.E., van den Akker, F., Warman, M.L. Mutations in the Transmembrane Natriuretic Peptide Receptor NPR-B Impair Skeletal Growth and Cause Acromesomelic Dysplasia, Type Maroteaux (2004). Am. J. Hum. Genet. 75, 27-34.

  • Hall, P.R., Zheng, R., Pusztai-Carey, M., van den Akker, F., Carey, P.R., & Yee, V.C. Expression and crystallization of several forms of the Propionibacterium shermanii transcarboxylase 5S subunit (2004). Acta Cryst. D60, 521-523.

  • Padayatti, P.S., Helfand , M.S., Totir, M.A., Carey, M.P., Hujer, H.M., Carey,P.R., Bonomo, R.A., & van den Akker, F. Tazobactam forms a stoichiometric trans-enamine intermediate in the E166A variant of SHV-1 beta-lactamase: 1.63 Å crystal structure (2004). Biochemistry, 43, 843-848.

  • Ramamurthy, V., Roberts, M., van den Akker, F., Niemi, G., Reh, T.A., Hurley, J.B. AIPL1, a protein implicated in Leber's congenital amaurosis, interacts with and aids in processing of farnesylated proteins (2003). PNAS 100, 12630-12635.

  • Chen, X., Bhandari, R., Vinkemeier, U., van den Akker, F., Darnell, J.E. Jr. & Kuriyan, J. A reinterpretation of the dimerization interface of the N-terminal domains of STATs (2003). Protein Science.,12, 361-365.

  • van den Akker, F. Detailed analysis of the atrial natriuretic factor receptor hormone binding domain crystal structure (2001). Can. J. Physiol. Pharmacol., 79, 692-704.

  • van den Akker, F. Structural insights into the ligand binding domains of membrane bound guanylyl cyclases and natriuretic peptide receptors (2001). J. Mol. Biol. 311, 923-937.

  • van den Akker, F., Zhang, X., Masaru, M., Huo, X., Misono, K.S., Yee, V.C. (2000) Crystal structure of the dimerized hormone binding domain of a guanylyl cyclase coupled receptor. Nature, 406, 101-104.

  • Chatterjee-Kishore, M., van den Akker, F., Stark, G.R. Association of STATs with relatives and friends (2000). Trends in Cell Biology 10, 106-111.

  • Chatterjee-Kishore, M., van den Akker, F., Stark, G.R. Adenovirus E1A down-regulates LMP2 transcription by interfering with the binding of STAT1 to IRF1 (2000). J. Biol. Chem. 275, 20406-20411.

  • van den Akker, F. & Hol, W.G.J. (1999) Difference density quality (DDQ): A method to assess the global and local correctness of macromolecular crystal structures. Acta Cryst. D55, 206-218.