Stadtman Tenure-Track Investigator
Structural Biochemistry Unit
30 Convent Dr. MSC 4370
Bethesda, MD 20892
Glycans (or polysaccharides) that are covalently linked to proteins and lipids modulate the host-microbe interface in the oral cavity and play an important role in health and disease. From microbe to host, glycan biosynthesis is catalyzed by a diverse family of enzymes called glycosyltransferases (GTs).
In the host
We study a family of GTs termed Polypeptide N-Acetylgalactosaminyltransferase (GalNAc-Ts) that initiate mucin-type O-glycosylation by transferring N-Acetylgalactosamine (GalNAc) from UDP-GalNAc to Thr/Ser residues of a protein substrate. Substrates include the mucin glycoproteins that endow the mucus lining the surface of the epithelium gel-like properties that are vital for protecting the underlying tissue from deleterious infection as well as physical and chemical damage. The glycan chains on mucus also underly the persistence of many commensal bacteria. Our lab uses structural and biochemical methods to answer the following questions:
- How do GalNAc-Ts recognize substrates? Specific substrates for many GalNAc-Ts have not been identified because the enzymes do not recognize a single consensus sequence or motif. To identify their substrates and better understand their biological functions, we are investigating the molecular basis of substrate preferences.
- What is the mechanism of active site alignment and catalysis? Our ultimate goal is to identify small molecule modulators of GalNAc-Ts to enable enhancement of those activities beneficial for health and to inhibit those which are harmful.
We study GTs that synthesize virulence factors in microbes that reside in the oral cavity. These factors include:
- Lipopolysaccharides (LPS, endotoxins) consisting of lipid A, core oligosaccharides, and O-polysaccharides (O-antigen). LPS coat the outer membrane of gram-negative bacteria and can elicit a strong immune response in the host. We are interested in understanding the mechanism of O-polysaccharide biosynthesis.
- Capsular polysaccharides (CPS) that coat the outer membranes of some bacteria and help them to evade host defenses such as phagocytosis. Currently, we are interested in GTs that synthesize CPS containing GalNAc and want to understand how these enzymes are evolutionarily distinct from metazoan GalNAc-Ts.
- Exopolysaccharides (EPS) are involved in biofilm formation. How are these structures synthesized?
Understanding the synthesis machinery of these molecules will help to identify potential antimicrobial targets.
Dr. Nadine Samara was born in New York City and has lived in Lebanon, Saudi Arabia and the United States. Upon graduating from the American University of Beirut with a B.S. in Chemistry, she returned to the United States and obtained a Ph.D. in Molecular Biophysics from The Johns Hopkins University School of Medicine. She then started her postdoctoral research as an NIGMS-PRAT Fellow at NIDDK/NIH. In 2015, Dr. Samara transitioned to a Staff Scientist Position at NIDCR/NIH, where she is now an Earl Stadtman Investigator and Chief of the Structural Biochemistry Unit. As a Distinguished Scholar at NIH, Dr. Samara will focus on building an inclusive and diverse environment within the lab and institute.
- Fernandez, A.J., Daniel, E. J. P., Mahajan, S.P., Gray, J.J. Gerken, T.A., Tabak, L.A. and Samara, N.L. (2019). The structure of the colorectal cancer-associated enzyme GalNAc-T12 reveals how non-conserved residues dictate its function. PNAS, vol. 116, pp. 20404-20410.
- Wu, J., Samara, N.L., Kuraoka, I., Yang, W. (2019). Evolution of Inosine-Specific Endonuclease V from Bacterial DNase to Eukaryotic RNase. Molecular Cell, vol. 76, pp. 1-13.
- Ji, S.*, Samara, N. L.*, Revoredo, L., Zhang, L., Tran, D. T., Muirhead, K., Tabak, L. A., Ten Hagen, K. G. (2018). A molecular switch orchestrates enzyme specificity and secretory granule morphology. Nature Communications, 9, 3508.
- Samara, N. L., & Yang, W. (2018). Cation trafficking propels RNA hydrolysis. Nature Structural & Molecular Biology, 25(8), 715–721.
- Samara N.L.*, Gao Y*, Wu J, Yang W (2017). Detection of Reaction Intermediates in Mg2+-Dependent DNA Synthesis and RNA Degradation by Time-Resolved X-Ray Crystallography. Methods Enzymol., 592, pp.283-327.
- Li C.L., Golebiowski F.M., Onishi Y., Samara N.L., Sugasawa K, Yang W. (2015). Tripartite DNA Lesion Recognition and Verification by XPC, TFIIH, and XPA in Nucleotide Excision Repair. Molecular Cell, vol. 59, issue 6, pp. 1025-34.
- Samara, N.L., Ringel, A.E., and Wolberger, C. (2012). A Role for Inter-subunit Interactions in Maintaining SAGA Deubiquitinating Module Structure and Activity. Structure, vol. 20, issue 8, pp.1414-24.
- Samara, N.L. and Wolberger, C. (2011). A New Chapter in the Transcription SAGA. Current Opinions in Structural Biology, vol. 21, issue 6, pp. 767-74.
- Samara, N.L.*, Datta, A.B.*, Berndsen, C.E., Zhang, X., Yao, T., Cohen, R.E., Wolberger, C. (2010). Structural Insights into the Assembly and Function of the SAGA Deubiquitinating Module. Science, vol. 328, pp.1025-29.