Dr Nancy Dahms
Research and Selected Publications

Research Interests

Our research investigates the molecular mechanisms underlying the functioning of mannose 6-phosphate receptors (MPRs) in mammalian cells. Two areas of research are currently in progress:

1. Structural Analysis of the Mannose 6-Phosphate Receptors (MPRs): A fundamental question in biochemistry today is how various proteins are targeted to their proper intracellular location. The targeting of lysosomal enzymes to lysosomes, which involves carbohydrate signals and receptors, is one of the best characterized systems for addressing this question. The transport of newly synthesized lysosomal enzymes to the lysosome in mammalian cells is dependent upon MPRs. Two distinct but homologous receptors, the insulin-like growth factor II/cation-independent MPR (IGF-II/CI-MPR) and the cation-dependent MPR (CD-MPR), have been identified.

The IGF-II/CI-MPR is a multifunctional protein that binds both mannose 6-phosphate (Man-6-P) on lysosomal enzymes and insulin-like growth factor II (IGF-II), a nonglycosylated polypeptide hormone that is essential for normal fetal growth. To better understand at the molecular level how these receptors function to bind and deliver lysosomal enzymes to the lysosome and how the IGF-II/CI-MPR functions upon binding IGF-II, we are utilizing site-directed mutagenesis to further localize the ligand binding sites and to identify amino acid residues which are essential for Man-6-P and IGF-II binding. In order to determine the 3-dimensional structure of the receptors, crystallographic studies are currently underway in collaboration with Dr. Jung-Ja Kim. These studies have led to a high resolution structure (1.8Å) of the extracytoplasmic domain of the CD-MPR.

2. Insulin-Like Growth Factor II and Mannose 6-Phosphate Receptors in Polarized Epithelial Cells: We are examining the factors which regulate the expression and cellular sorting of the MPRs and their ligands in polarized intestinal epithelial cells during development and cellular differentiation. Enterocytes are rapidly proliferating cells of the intestinal mucosa which perform important functions in nutrient and ion transport. An in vitro cell culture system using Caco-2 cells is being used to address the role MPRs, lysosomal enzymes, IGF-II, and IGF binding proteins have in the normal growth, differentiation, and function of enterocytes. In addition, we are analyzing the mechanisms by which the MPRs are expressed in a polarized fashion on the cell surface of Caco-2 cells.

Linda Olson, Ph.D., a postdoctoral fellow in the laboratory, is currently working on the generation of diffraction-quality crystals of the MPRs and on the identification of residues involved in ligand binding.

Guangjie Sun, a graduate student in the laboratory, is concentrating his efforts on defining the interactions between the MPRs and non-Man-6-P-containing ligands.

Sreelatha Reddy, Ph.D., a postdoctoral fellow in the laboratory, is currently characterizing a novel MPR-like protein.

"Identification of a Low-Affinity Mannose 6-Phosphate Binding Site in Domain 5 of the Cation-Independent Mannose 6-Phosphate Receptor." S. T. Reddy, W. Chai, R. A. Childs, J. D. Page, T. Feizi, and N. M. Dahms J. Biol. Chem. 279, 38658-38667 (2004).

"The N-Terminal Carbohydrate Recognition Site of the Cation-Independent Mannose 6-Phosphate Receptor". L. J. Olson, N. M. Dahms, and J.-J. P. Kim. J. Biol. Chem. 279, 34000-34009 (2004).

"Structure of the uPAR, Plasminogen, and Sugar Binding Sites of the 300 kDa Mannose 6-Phosphate Receptor". L. J. Olson, R. Yammani, N. M. Dahms, and J.-J. P. Kim EMBO J 23, 2019-2028 (2004).

"Biochemical and Functional Properties of the Full-Length Cation-Dependent Mannose 6-Phosphate Receptor Expressed in Pichia pastoris". S. T. Reddy, S.N. Kumar, A. L. Haas, and N. M. Dahms Biochem. Biophys. Res. Commun. 309, 643-651 (2003).

"Mannose 6-Phosphate Receptors: New Twists in the Tale." P. Ghosh, N.M. Dahms and S. Kornfeld Nature Rev. Mol. Cell Biol. 4, 202-212 (2003)

"P-Type Lectins." N.M. Dahms and M.K. Hancock Biochem. Biophys. Acta 1572, 317-340 (2002)

"Localization of the Carbohydrate Recognition Sites of the Insulin-Like Growth Factor II/Mannose 6-Phosphate Receptor to Domains 3 and 9 of the Extracytoplasmic Region." M.K. Hancock, R.D. Yammani, N.M. Dahms J. Biol. Chem. 277(49), 47205-12(2002)

"High-Level Expression and Characterization of a Secreted Recombinant Cation-dependent Mannose 6-Phosphate Receptors in Pichia pastoris." S.T. Reddy and N.M. Dahms Protein Expr. Purific. Nov 26(2), 290-300 (2002)

"Identification of Residues Essential for Carbohydrate Recognition by the Insulin-Like Growth Factor II/Mannose 6-Phosphate Receptor." M. K. Hancock, D. J. Haskins, G. Sun, and N. M. Dahms J. Biol. Chem. 277(13), 11255-11264 (2002)

"Twists and Turns of the Cation-Dependent-Mannose 6-Phosphate Receptor: Ligand-Bound versus Ligand-Free Receptor." L. J. Olson, J. Zhang, N. M. Dahms, and J.-J. P. Kim J. Biol. Chem. 277(12), 10156-10161 (2002)

"The Basolateral Sorting Signal of the 300kDa Mannose 6-Phosphate Receptor" D. A. Wick, B. Seetharam, and N. M. Dahms Am. J. Physiol. 282, G51-G60 (2002)

"Recognition of Dictyostelium discoideum Lysosomal Enzymes is Conferred by the Amino-Terminal Carbohydrate Binding Site of the Insulin-Like Growth Factor II/Mannose 6-Phosphate Receptor" P. G. Marron-Terada, M. K. Hancock, D. J. Haskins, and N. M. Dahms Biochemistry 39, 2243-2253 (2000).

"Mutational Analysis of the Binding Site Residues of the Bovine Cation-Dependent Mannose 6-Phosphate Receptor" L. J. Olson, M. K. Hancock, D. Dix, J.-J. P. Kim, and N. M. Dahms J. Biol. Chem. 274, 36905-36911(1999).

"Structural Basis for Recognition of Phosphorylated High Mannose Oligosaccharides by the Cation-Dependent Mannose 6-Phosphate Receptor" L. J. Olson, J. Zhang, Y. C. Lee, N. M. Dahms, and J.-J. P. Kim J. Biol. Chem. 274, 29889-29896 (1999).

"Biosynthesis and Secretion of the Mannose 6-Phosphate Receptor and Its Ligands in Polarized Caco-2 Cells" D. A. Wick, B. Seetharam, and N. M. Dahms Am. J. Physiol. 277, G506-G514 (1999).

"Characterization of Truncated and Glycosylation-Deficient Forms of the Cation-Dependent Mannose 6-Phosphate Receptor Expressed in Baculovirus-Infected Insect Cells". P.G. Marron-Terada, K.E. Bollinger, and N. M. Dahms. Biochemistry 37, 17223-17229 (1998).

"Molecular Basis of Lysosomal Enzyme Recognition: Three-Dimensional Structure of the Cation-Dependent Mannose 6-Phosphate Receptor". D.L. Roberts, D.J. Weix, N.M. Dahms, and J.-J.P. Kim. Cell 93, 639-648 (1998).

"The Two Mannose 6-Phosphate Binding Sites of the Insulin-like Growth Factor-II/Mannose 6-Phosphate Receptor Display Different Ligand Binding Properties". P. G. Marron-Terada, M.A. Brzycki-Wessell, and N.M. Dahms. J. Biol. Chem. 273, 22358-22366 (1998).

"Insulin-like Growth Factor II/Cation-Independent Mannose 6-Phosphate Receptor and Lysosomal Enzyme Recognition". N.M. Dahms. Biochem. Soc. Trans. 24, 136-141 (1996).

"Expression of Insulin-like Growth Factor (IGF-I) Receptors, IGF-II/Cation-Independent Mannose 6-Phosphate Receptors (CI-MPRs), and Cation-Dependent MPRs in Polarized Human Intestinal Caco-2 Cells". N.M. Dahms, B. Seetharam, and D.A. Wick. Biochem. Biophys. Acta 1279 84-92 (1996).

"Expression of Insulin-like Growth Factor II (IGF-II) and IGF Binding Proteins in Differentiating Human Intestinal Caco-2 Cells". Y. Zhang, D.A. Wick, B. Seetharam, and N.M. Dahms. Am. J. Physiol. 269, E804-E813 (1995).

"The Bovine Mannose 6-Phosphate/Insulin-Like Growth Factor II Receptor. Localization of the IGF-II Binding Site to Domains 5-11". N.M. Dahms, D. Wick, and M.A. Bryzcki-Wessell. J. Biol. Chem. 269, 3802-3809 (1994).

"The Bovine Mannose-6-Phosphate/Insulin-like Growth Factor Receptor. The Role of Arginine Residues in Mannose 6-Phosphate Binding". N.M. Dahms, P.A. Rose, J.D. Molkentin, Y. Zhang, and M.A. Brzycki. J. Biol. Chem. 268, 5457-5463 (1993).

Last modified on: Thursday, 09-Sep-2004 13:05:56 CDT