Raquel L. Lieberman Assistant Professor Office: IBB 1303 Phone: 404-385-3663 Fax: 404-894-2995 E-mail Raquel Lieberman The Lieberman Research Group

B. Sc. Massachusetts Institute of Technology, 1998; M. S. Northwestern University, 1999; Ph. D. Northwestern University, 2005; Postdoctoral Research Fellow, Harvard Medical School, Brigham & Women's Hospital, Brandeis University, 2005-2007

American Chemical Society Nobel Laureate Signature Award for Graduate Education in Chemistry (2006), NIH Postdoctoral Research Fellowship (2005), Merck Index Award for Excellence in Chemistry (1998)

Research Interests

We are interested in the molecular details of how cells survive by recognizing and responding to intracellular signals. Eukaryotic cells employ several mechanisms to maintain homeostasis, and if these systems are mis-regulated, changes in metabolite concentrations or protein production/folding eventually lead to a host of diseases. In addition, some of these pathways exist in and are exploited by bacterial pathogens and viruses to gain entry into eukaryotic cells. We seek to understand the details of structure, function, and mechanism of proteins involved in these highly regulated pathways, focusing on enzymes that perform hydrolysis reactions in an unexpected chemical environment: within lipid membrane or near the surface of membranes. In the long term, we hope to identify small molecule inhibitors to modulate these activities and prevent diseases associated with aberrant signaling behavior.

Our methods focus on protein crystallography, biochemical and biophysical characterization, in silico modeling, and drug design.

Protein misfolding and mistrafficking.

Two projects in this subgroup include lysosomal enzymes acid-β-glucosidase and acid-α-galactosidase, which hydrolyze bioactive sphingolipids at the lysosomal membrane. Genetically inherited mutations in these enzymes lead to lipid storage disorders Gaucher Disease and Fabry Disease. In most cases the mutations occur remote from the active site of the enzyme and partial activity can be measured in vitro. However, in a cell, the mutant enzyme remains in the endoplasmic reticulum where it was synthesized, is then targeted for degradation, and consequently never reaches the lysosome. The goals of these projects are to elucidate the biophysical effects of specific mutations, and to design novel small molecules called pharmacological chaperones to ameliorate trafficking of the partially active mutant enzyme to the lysosome.

Intramembrane proteolysis.

Projects in this subgroup focus on the structure and function of newly discovered integral membrane enzymes that perform proteolysis within the cell membrane, so-called "intramembrane proteases". The substrates for these proteases are membrane-spanning signaling peptides that enable mature, folded proteins to reach their final subcellular destinations. The leftover proteolyzed peptide fragments help report to the immune system about a particular cell's overall state of health, a process that is exploited by viruses for infection. Incorrectly proteolyzed fragments can also aggregate to form plaques, which have been implicated in neurodegenerative disorders like Alzheimer disease. The biological functions of most intramembrane proteases are not known, yet they are conserved among all kingdoms of life. Finally, little is also known about the biochemistry of hydrolytic chemistry within the confines of the lipid membrane, including structural elements that govern access of the hydrophobic substrate to a hydrophilic active site, substrate specificity, and kinetics of hydrolysis.

Relevant publications:

"Structure of acid-β-glucosidase with pharmacological chaperone provides insight into Gaucher disease," Lieberman, R. L.; Wustman, B. A.; Huertas, P.; Powe, A. C., Jr.; Pine, C. W.; Khana, R.; Schlossmacher, M. G.; Ringe, D.; Petsko, G. A., Nat. Chem. Biol., 2007, 3, 101-107.

"From rhomboid function to structure and back again," Lieberman, R. L.; Wolfe, M. S., Proc. Natl. Acad. Sci., 2007, 104, 8199-8120.

"Intramembrane protease poses for photoshoot," Lieberman, R. L.; Wolfe, M. S., Proc. Natl. Acad. Sci. USA, 2007, 104, 401-402.