Lawrence A. Tabak, D.D.S., Ph.D., Chief
The Section on Biological Chemistry conducts basic research on biosynthesis, structure and function of glycoproteins, placing a special emphasis on mucin-type O-glycans.
Our laboratory studies the functions and biosynthesis of O-glycans. Mucin- glycoproteins are heavily decorated with carbohydrate side-chains, termed O-glycans, which are often clustered within repeating amino acids sequences of the protein (tandem repeats).
Functionally, membrane-bound mucins are involved in signal transduction events whereas secreted mucins contribute to the formation of extracellular matrix or to the gel-like mucus coat which envelopes mucosal surfaces of the body thereby forming the most exterior face of the innate immune system. Although it is known that O-glycans are ubiquitous among proteins, the precise nature of the “O-glycome” remains to be defined. We have approached this by both top-down and bottom-up proteomic studies as well as investigations of the substrate specificities of the multi-gene family of enzymes that are responsible for the formation of O-glycans, the UDP-GalNAc:polypeptide N-Acetylgalactosaminyltransferases (GalNAcTs). Although no consensus amino acid sequence has emerged that is both necessary and sufficient for O-glycan formation, two classes of GalNAcTs – those which readily glycosylate peptide directly (“naked” or unglycosylated peptide) and those which will only act on glycopeptide substrates (peptides previously decorated with O-glycans) have been identified. This strongly implies that there is a hierarchical acquisition of O-glycans. Why Nature requires such precision in selecting which specific amino acids will be glycosylated is not yet known, although it may have to do with the ability of surface carbohydrates to form a “polyvalent array”, enabling cells or molecules to sample each other before entering into specific, long-term relationships via high affinity interactions with either carbohydrates and/or proteins.
Our major efforts are focused on the roles played by GalNAc-Ts during development and furthering our understanding of the mechanisms that underlie GalNAc-T function. Specific projects include:
- Determination of the structural elements that guide the substrate specificity of GalNAc-Ts (in collaboration with Tom Gerken, CWRU)
- Analysis of O-glycan function in endocrine cell differentiation
- Identification of the molecular mechanisms that regulate GalNAcTs transport and activity through the biosynthetic pathway
- Analyzing the role(s) played by GalNAc-Ts in lipid metabolism (in collaboration with A.G. Holleboom, Jan Albert Kuivenhoven, and colleagues, University of Amsterdam), Kelly Ten Hagen, NIDCR, and Henrik Clausen, University of Copenhagen
Tabak Group Members
Please click on individual lab members’ names to review their ongoing efforts in greater detail:
Nadine Samara, PhD – Staff Scientist
Duy Tran, PhD – Staff Scientist
Gaetan Herbomel - Visiting Fellow
Amber Famiglietti – Post Bacc IRTA
Lawrence A. Tabak, D.D.S., Ph.D
Senior Investigator, NIDCR
Principal Deputy Director, NIH
30 Convent Dr.
Building 30, Room 524
Bethesda, MD 20892
National Institutes of Health
Building 1, Room 126
Bethesda, MD 20892-2290
Education/Previous Training and Experience
Dr. Tabak was appointed as the principal deputy director of the NIH on August 23, 2010. Previously he served as acting principal deputy director of the NIH from November 13, 2008 through August 14, 2009. Named as the director of the National Institute of Dental and Craniofacial Research (NIDCR) in September 2000, he held that post through August 2010. Prior to joining NIH, Dr. Tabak served as the senior associate dean for research and professor of dentistry and biochemistry & biophysics in the School of Medicine and Dentistry at the University of Rochester in New York. A former NIH MERIT recipient, Dr. Tabak has received several honors and awards for his work including being elected as a member of the Institute of Medicine of the National Academies. He has also received teaching awards for his work with both graduate and medical students.
Revoredo, L., Wang, S. Bennett, E.P., Clausen, H., Moremen, K.W., Jarvis,D.L. Ten Hagen, K.G. Tabak, L.A., and Gerken, T.A., Mucin-type O-glycosylation is controlled by short- and long-range glycopeptide substrate recognition that varies among members of the polypeptide GalNAc transferase family. Glycobiology 2015, 1–17 doi: 10.1093/glycob/cwv10
Tian, E, Stevens, S.R., Springer, D.A., Anderson, S.A. Starost, M.F., Patel, V., Ten Hagen, K.G., and Tabak, L.A. Galnt1 is required for normal heart valve development and cardiac function. PLoS One, 10(1): e0115861.doi:10.1371/journal.pone.0115861, 2015
Gomez, H., Rojas, R., Patel, D., Tabak, L.A., Lluch, J., and Masgrau, L., A computational and experimental study of O-glycosylation. Catalysis by human UDP- GaINac polypeptide: GaINac transferase-T2. Org. Biomol. Chem., 12: 2645-2655, 2014.
Bennett, E.P., Mandel, U., Clausen, H., Gerken, T.A., Fritz, T.A., and Tabak, L.A. Control of Mucin-Type O-Glycosylation – A Classification of the Polypeptide GalNAc-transferase Gene Family, Glycobiology (2011)22:736-756, 2012.
Holleboom,A.G., Karlsson,H., Lin,R.-S., Beres, T.M., Sierts, J.A., Herman, D.S., Stroes, E.S.G., Aerts, J.M., Kastelein, J.J.P., Motazacker, M.M., Dallinga-Thie, G.M., Levels, J.H.M., Zwinderman, A.H., Seidman, J.G., Seidman, C.E., Ljunggren, S., Lefeber, D.J., Morava, E., Wevers, R.A., Fritz, T.A., Tabak, L.A., Lindahl, M., Hovingh, G.K., and Kuivenhoven, J.A. Heterozygosity for a Loss-of-Function Mutation in GALNT2 Improves Plasma Triglyceride Clearance in Man. Cell Metabolism 14:811–818, 2011.
Gerken, T.A., Jamison, O., Perrine, C.L., Collette, J.C., Moinova, H., Ravi, L., Markowitz, S.D.,, Shen, W., Patel, H., and Tabak, L.A. Emerging paradigms for the initiation of mucin type protein O-glycosylation by the polypeptide GalNAc transferase (ppGalNAc T) family of glycosyltransferases. J. Biol. Chem. 286:14493-14507, 2011.
Tabak, L. A. The Role of Mucin-type O-glycans in Eukaryotic Development. Seminars in Cell and Developmental Biology, 21:616-621, 2010.
Miwa, HE, Gerken, TA, Jamison, O and LA Tabak . Isoform-specific O-glycosylation of osteopontin and bone sialoprotein by polypeptide N-acetylgalactosaminyltransferase-1. J. Biol. Chem., 2010 285; 1208 –1219, 2010.
Perrine, CL, Ganguli, A, Wu, P, Bertozzi, CR, Fritz,TA, Raman, J, Tabak, LA and TA Gerken. Glycopeptide-preferring polypeptide GalNAc transferase 10 (ppGalNAc T10), involved in mucin-type O-glycosylation, has a unique GalNAc-O-Ser/Thr-binding site in its catalytic domain not found in ppGalNAc T1 or T2. J. Biol. Chem., 284; 20387-20397, 2009.
Raman, J, Fritz, TA., Gerken, TA, Jamison, O, Live, D, Liu,M and Tabak, LA. The catalytic and lectin domains of UDP-GalNAc:polypeptide α-N Acetylgalactosaminyltransferase function in concert to direct glycosylation site selection. J. Biol Chem., 283; 22942-22951, 2008.
Tenno M, Ohtsubo K, Hagen FK, Ditto D, Zarbock A, Schaerli P, von Andrian UH, Ley K, Le D, Tabak LA, Marth JD. Initiation of protein O glycosylation by the polypeptide GalNAcT-1 in vascular biology and humoral immunity. Mol Cell Biol (27): 8783-96, 2007.
Fritz TA, Raman J, Tabak LA. Dynamic association between the catalytic and lectin domains of human UDP-GalNAc:polypeptide α-N-acetylgalactosaminyltransferase-2. J Biol Chem. 281(13):8613-9, 2006.