Dr. Heidi Erlandsen
Heidi Erlandsen, PhD
Institute of Oral Health Research
Dept. of Periodontology
School of Dentistry at UAB
1919 7th Avenue South, SDB 716
Birmingham, AL 35294-0007
Phone: (205) 996-9687
FAX: (205) 996-5109
Research Focus: Protein crystallography, molecular mechanisms of cell signaling, metabolic disease.
Structural Delineation of Pleiotrophin Signaling
Pleiotrophin (PTN) is a secreted heparin-binding cytokine that signals diverse functions, including lineage-specific differentiation of glial progenitor cells, neurite outgrowth, and angiogenesis. The gene expression of PTN, also known as HB-GAM, and osteoblast-specific factor 1 (OSF-1) is found in cells in early differentiation during developmental periods and is up-regulated in cells with an early differentiation phenotype in wound repair. ptn is also a proto-oncogene, which is strongly expressed in different human tumor cells and expression of the ptn gene in tumor cells in vivo accelerates growth and stimulates tumor angiogenesis. PTN has been proposed to act by binding to the transmembrane receptor tyrosine phosphatase (RPTP beta/zeta), resulting in a loss of intracellular RPTP phosphatase activity, putatively through ligand-induced dimerization of the active D1 domain of RPTPbeta/zeta. Pleiotrophin is the first physiological ligand to be discovered for the tyrosine phosphatase receptor family. We are working towards elucidation of the three-dimensional structures of the protein complexes involved in the PTN signaling pathway.
Structural investigation of neurotransmitter biosynthesis and regulation
Cateholaminergic (dopaminergic, noradrenergic and adrenergic) and serotonergic neurotransmission are the primary targets for drugs used to treat psychiatric and mental disorders such as depression, schizophrenia and Parkinson's disease. The enzymes tyrosine and tryptophan hydroxylase control the cellular levels of these neurotransmitters since they catalyze the rate-limiting steps of neurotransmitter biosynthesis. The aim of the research is to understand the cellular regulation of the human neurotransmitter biosynthetic enzymes found in the brain and liver/kidney, by structurally characterizing the regulatory protein modifications and interactions known to be physiologically significant. These structural studies will be of fundamental importance to future pharmacological studies of neurological diseases.
Selected publications: (PubMed for Dr. Heidi Erlandsen)
Erlandsen H., Fusetti F., Martínez A., Hough E., Flatmark T., Stevens R. C. (1997) "Crystal structure of the catalytic domain of human phenylalanine hydroxylase reveals the structural basis for phenylketonuria" Nature Structural Biology, 4, 995-1000.
Fusetti F., Erlandsen H., Flatmark T., Stevens R. C. (1998) "Structure of tetrameric human phenylalanine hydroxylase and its implications for phenylketonuria" Journal of Biological Chemistry, 273, 16962-16967.
Erlandsen H., and Stevens R. C. (1999) “The Structural Basis of Phenylketonuria” Molecular Genetics and Metabolism, 68, 103-125.
Erlandsen H., Abola E. E., Stevens R.C. (2000) “Combining Structural Genomics and Enzymology: Completing the Picture in Metabolic Pathways and Enzyme Active Sites” Current Opinion in Structural Biology, 10, 719-730.
Erlandsen H. and Stevens R.C. (2001) “A structural hypothesis for BH4 responsiveness in phenylketonuria patients” Journal of Inherited Metabolic Disease, 24, 213-230.
Erlandsen H., Kim J.Y., Dries D, Han A., Volner A., Abu-Omar M.M., Stevens R.C. (2002) “Structural Comparison of Bacterial and Human Iron-dependent Phenylalanine Hydroxylases: Similar Fold, Different Stability and Reaction Rates” Journal of Molecular Biology, 320, 645-661.
Erlandsen H. and Stevens R.C. (2002) “Structural Studies of Phenylalanine Hydroxylase” External Update to Chapter 77 (Hyperphenylalaninemia: Phenylalanine Hydroxylase Deficiency) Metabolic & Molecular Bases of Inherited Disease (8 Ed., online version).
Wang L., Erlandsen H., Haavik J., Knappskog P.M., Stevens R.C. (2002) “Three-dimensional structure of human tryptophan hydroxylase and its implications for the biosynthesis of the neurotransmitters serotonin and melatonin” Biochemistry, 41, 12569-12574.
Charles R. Scriver, Mélanie Hurtubise, David Konecki, Manyphong Phommarinh, Lynne Prevost, Heidi Erlandsen, Raymond C. Stevens, Paula J. Waters, Shannon Ryan, David McDonald, Christineh Sarkissian (2003) “PAHdb 2003: What a locus-specific knowledgebase can do”, Human Mutation, 21: 333-344.
Erlandsen H., Patch M.G., Gamez A., Straub M. and Stevens R.C. (2003) “Structural Studies on Phenylalanine Hydroxylase and Implications Towards Understanding and Treating Phenylketonuria”, Pediatrics,112: 1557-1565.
Marcin Grynberg, Heidi Erlandsen and Adam Godzik (2003) “HEPN: domain involved in NTP binding and present in antibiotic resistance proteins in bacteria and human gene responsible for a neurodegenerative disease”, Trends in Biomedical Sciences,.28: 224-226.
Erlandsen H. and Blau N. (2004) “The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency”. Molecular Genetics and Metabolism. 82:101-111.
Kim W, Erlandsen H, Surendran S, Stevens RC, Gamez A, Michols-Matalon K, Tyring SK, Matalon R. (2004) “Trends in enzyme therapy for phenylketonuria”. Mol Ther.10: 220-224.
Erlandsen H., Pey A.L., Gámez A., Pérez B., Desviat L. R., Aguado C., Koch R., Surendran S., Tyring S., Matalon R., Scriver C. R., Ugarte M., Martínez A. and Stevens R. C. (2004) “Correction of kinetic and stability defects by the cofactor BH4 in PKU patients with certain phenylalanine hydroxylase mutations”. Proceeding of the National Academy of Sciences USA. 101:16903-16908.
Erlandsen H. (2006) “Molecular Mechanisms of tetrahydrobiopterin-responsiveness”. Book chapter. “PKU and BH4 – Advances in Phenylketonuria and Tetrahydrobiopterin Research”, Ed.: N. Blau, SPS Publications, Heilbronn, Germany.
Hallberg BM., Ericsson UB., Johnson KA., Andersen NM., Douthwaite S., Nordlund P., Beuscher AE. 4th, Erlandsen H. (2006) The structure of the RNA m5C methyltransferase YebU from Escherichia coli reveals a C-terminal RNA-recruiting PUA domain. J. Mol. Biol. 360:774-87.
Gurmu D., Lu J., Johnson KA., Nordlund P., Holmgren A., Erlandsen H. (2007) The crystal structure of the protein YhaK from Escherichia coli reveals a new subclass of redox sensitive enterobacterial bicupins. Manuscript submitted.