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Michael E. Hodsdon, MD, PhD
Associate Professor of Laboratory Medicine and Pharmacology
Associate Director,Clinical Chemistry Laboratory

Office: CB-462B; 203-737-2674
Lab: CB-440E; 203-737-2684, 203-737-2830
Administrative Assistant (Vilma Moreno): 203-737-5934
michael.hodsdon@yale.edu

1989, B.S., Indiana Univeristy
1997, M.D., Ph.D., Washington University in St. Louis
1998-2000, Laboratory Medicine Residency, Yale-New Haven Hospital
2000-2001, Research Fellowship, Yale University

Community of Science Biosketch

Hodsdon Laboratory Web Page

Research Interests
Our primary scientific interest is to better understand how the structural and biophysical properties of proteins contribute to their role in pathophysiology of human disease. NMR spectroscopy is a central tool in our research program used to determine the three-dimensional structures of proteins in solution and to monitor a variety of biophysical properties under physiological conditions. At the moment, we are investigating a number of biomedically important protein systems, which are briefly summarized below. A detailed description of our research efforts can be found on our Laboratory Web Page.

The Structural Basis of Prolactin Receptor Recognition. The long-term goal of this project is to delineate the specific structural and functional interactions involved in prolactin receptor (PRLr) recognition and signal transduction. Although best known for its traditional role as a pituitary-derived hormone, recent research has established important autocrine/paracrine functions of prolactin (PRL) in the growth and development of a diversity of tissues. PRL and its receptor are expressed in cancers of the breast, prostate and female reproductive tract. PRL has mitogenic and angiogenic function in these tumors and increases cancer cell motility. Whereas a vast majority of pituitary-derived PRL is secreted as the full-length, unmodified protein, in peripheral tissue glycosylated and phosphorylated variants of PRL are found. Research has demonstrated functional consequences of these modifications, some of which may act to counter the tumorigenic effects of unmodified PRL. Our primary objective is to identify, at an atomic level, the precise intermolecular interactions responsible for PRL receptor recognition specificity. Towards this goal, we have determined the tertiary structure of human PRL using NMR spectroscopy. We hypothesize that distinct subsets of surface residues are responsible for differences in receptor recognition specificity displayed by PRL and its variants towards PRLr isoforms. Our research will allow the use of site-directed mutagenesis to isolate individual interactions between PRL variants and receptor isoforms and will eventually aid the development of potential therapeutic agents designed to modulate specific activities of PRL, including PRLr antagonists, which will have significance for the treatment of breast and prostate cancer.

The GLUT4-tethering protein, TUG. This project focuses on the interactions between the insulin-regulated glucose transporter, GLUT4, found in muscle and adipose cells and a recently discovered protein, TUG, that regulates GLUT4 trafficking. Discovered by our collaborator, Dr. Jonathan Bogan, TUG binds directly to GLUT4-containing vesicles and tethers them intracellularly. In response to insulin, TUG releases GLUT4 allowing translocation to the plasma membrane. Like many other proteins, TUG is composed of a modular array of independent protein domains. Our long term goal is to determine the tertiary structures of these TUG domains, to structurally characterize their interactions with each other and with a number of associated proteins, and ultimately to develop a detailed molecular model for TUG-regulated GLUT4 trafficking. A combination of sequence analysis and experimental studies has identified a number of ubiquitin-like (UBL) domains in TUG. We have chosen these UBL domains as the initial focus of our structural studies because of (1) their demonstrated functional importance in TUG-mediated GLUT4 tethering and release, (2) the clear delineation of their structural domain boundaries based on sequence alignment, and (3) a pre-existing knowledge base of their potential interactions partners based on the conserved functions of homologous UBL domains in other proteins. The results of these studies will benefit diabetes research both by contributing to a better understanding of the cellular mechanism for insulin-regulated GLUT4 trafficking, and also by structurally characterizing novel targets for the rational design of pharmaceutical agents with the potential to modulate cellular glucose uptake.

Polymorphic Drug Metabolizing Enzymes. Research over the past 30 years has demonstrated striking genetic variability in the enzymatic pathways used to metabolize xenobiotics (drugs, poisons, pollutants, etc.) in the human body. This metabolic diversity complicates the administration of pharmaceutical agents to combat disease, resulting in variable levels of efficacy and toxicity from the same dosage of medications applied across a population. Ideally, the selection and dosing of individual medications would be specifically tailored to a predicted response within an individual. The scientific study of this genetic diversity and its relation to the administration of pharmaceuticals is the focus of the developing field of pharmacogenetics. One common biological mechanism for generating diversity in metabolic pathways involves inherited polymorphisms in the protein sequence of enzymes, which appear to target the polymorphic proteins for intracellular degradation. We would like to understand the structural and biophysical mechanisms by which genetic polymorphisms within the protein sequences of these enzymes modulate their relative role in drug metabolism and, consequently, on the variable efficacy and toxicity of administered pharmaceuticals. Our work so far has concentrated on the enzyme, thiopurine methyltransferase (TPMT), which metabolizes the class of 6-thiopurine medications, including 6-mercaptopurine, 6-thioguanine and azathioprine. Large variations of TPMT activity exist in humans and a variety of genetic polymorphisms in the TPMT protein sequence have been identified that target the allelic variants for proteasomal degradation. We have determined the three-dimensional structure of TPMT using NMR spectroscopy and characterized the consequences of ligand-binding on the conformation and molecular dynamics of the polypeptide backbone. We are currently analyzing the consequences of the polymorphic mutations on the structural and functional properties of TPMT in order to characterize the molecular basis for increased susceptibility to intracellular degradation.

Publications

Devine, L., Thakral, D., Nag, S., Dobbins, J., Hodsdon, M.E. and Kavathas, P.B. (2006) Mapping the binding site on CD8b for MHC Class I reveals mutants with enhanced binding. J. Immunol. 177, 3930 – 3938.

Murphy J.W., Cho Y., Sachpatzidis A., Fan C., Hodsdon M.E. and Lolis E. (2007) Structural and functional basis of CXCL12 (stromal cell-derived factor-1alpha ) binding to heparin. J. Biol. Chem. [Epub ahead of print].

Keeler C., Jablonski E.M., Albert Y.B., Taylor B.D., Myszka D.G., Clevenger C.V. and
Hodsdon M.E. (2007) The Kinetics of Binding Human Prolactin, but Not Growth Hormone, to the Prolactin Receptor Vary over a Physiologic pH Range. Biochemistry [Epub ahead of print].

Tettamanzi, M.C., Yu, C., Bogan, J.S. and Hodsdon, M.E. (2005) Solution structure and backbone dynamics of an N-terminal ubiquitin-like domain in the GLUT4-tethering protein, TUG. Biochemistry (submitted).

Mao, Y., Semic-Matuglia, F., DiFiore, P.P., Polo, S., Hodsdon, M.E.* and De Camilli, P.* (2005) De-ubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain. Proc. Natl. Acad. Sci. U.S.A. (in press). *co-corresponding authors

Hsiao AL, Santucci KA, Seo-Meyer P, Mariappan MR, Hodsdon ME, Banasiak KJ, Baum CR. (2005) Pediatric fatality following ingestion of dinitrophenol: post-mortem identification of a “dietary supplement”. J. Toxicol. Clin. Toxicol. 43(4), 281 – 285.

Kritzer, J.A., Hodsdon, M.E. and Schepartz, A. (2005) Solution structure of a β-peptide ligand for hDM2. J. Amer. Chem. Soc. 127(12), 4118 – 4119.

Scheuermann, T.H., Keeler, C. and Hodsdon, M.E., (2004) Consequences of binding an S-adenosyl-methionine analogue on the structure and dynamics of the thiopurine methyltransferase protein backbone. Biochemistry 43(38), 12198 – 12209.

Kritzer, J.A., Hodsdon, M.E., Lear, J.D., Schepartz, A. (2004) Specific recognition of hDM2 by a rationally designed β-peptide. J. Amer. Chem. Soc. 126(31), 9468 – 9469.

Devine, L., Hodsdon, M.E., Rogozinski, L, Soundararajan, U., Daniels, M.A., Jameson, S.C. and Kavathas, P.B. (2003) Location of the epitope for an anti-CD8α antibody 53.6.7 which enhances CD8αβ-MHC class I interaction inicates that enhancement involves stabilization of a specific CD8 conformation. Immunology Letters 93(2-3), 123-130.

Keeler, C., Hodsdon, M.E., Dannies, P.S. (2003) Is there structural specificity in the reversible protein aggregates stored in secretory granules? J. Mol. Neuroscience 22(1-2), 43 – 50.

Scheuermann, T.H., Lolis, E. and Hodsdon, M.E. (2003) Tertiary structure of thiopurine methyltransferase from Pseudomonas syringae, the bacterial orthologue of a polymorphic, drug-metabolizing enzyme. J. Mol. Biol. 333(3) 573-585.

Keeler, C., Dannies, P.S. and Hodsdon, M.E. (2003) The tertiary structure and backbone dynamics of human prolactin. J. Mol. Biol. 328(5), 1105-1121.

Sankoorikal, B.J., Zhu, Y.L., Hodsdon, M.E., Lolis, E. and Dannies, P.S. (2001) Aggregation of human wild-type and H27A-prolactin in solution and in cells: roles of Zn2+, Cu2+, and pH. Endocrinology 143, 1302-1309.

Hodsdon, M.E. and Frieden, C. (2001) The Intestinal Fatty Acid-Binding Protein: The Folding Mechanism as Determined by NMR Studies. Biochemistry 40, 732-742.

Steele, R.A., Emmert, D.A., Kao J., Hodsdon, M.E., Frieden, C. and Cistola, D.P., (1997) The Solution Structure of a Helix-less Variant of Intestinal Fatty Acid-Binding Protein. Protein Science 7, 1332-1339.

Hodsdon, M.E. and Cistola, D.P. (1997) Ligand Binding Alters the Backbone Mobility of Intestinal Fatty Acid-Binding Protein as Monitored by 15N NMR Relaxation. Biochemistry 36, 2278-2290.

Hodsdon, M.E. and Cistola, D.P. (1997) Discrete Backbone Disorder in the Nuclear Magnetic Resonance Structure of Apo Intestinal Fatty Acid-Binding Protein: Implications for the Mechanism of Ligand Entry. Biochemistry 36, 1450-1460.

Hodsdon, M.E., Ponder, J.W. and Cistola, D.P. (1996) The NMR Solution Structure of Intestinal Fatty Acid-Binding Protein Complexed with Palmitate: Application of a Novel Distance Geometry Algorithm. J. Mol. Biol. 264, 585-602.

Hodsdon, M.E., Toner, J.J. and Cistola, D.P. (1995) 1H, 13C, and 15N Assignments and Chemical Shift-Derived Secondary Structure of Intestinal Fatty Acid-Binding Protein. J. Biomol. NMR 6, 198-210.

Hodsdon, M.E., Toner, J.J. and Cistola, D.P. (1994) Sequence-Specific 1H, 13C, and 15N Resonance Assignments for Intestinal Fatty Acid-Binding Protein Complexed with Palmitate (15.4 kDa). In Proceedings of Stable Isotope Applications in Biomolecular Structure and Mechanisms, Los Alamos National Laboratory, New Mexico, p. 340.