Dr. Daniel N. Hebert
Associate Professor, Biochemistry and Molecular Biology
Adjunct Associate Professor of Chemistry

Protein folding, quality control and degradation in the cell

dhebert@biochem.umass.edu
Office: (413) 545-0079
Lab: (413) 545-4335, 545-4021, 545-4834

Lab Home Page

Background and Training

Ph.D.: University of Massachusetts Medical Center
Postdoctoral training: Yale University School of Medicine

Research Summary

The focus of my laboratory is to understand the processes involved in the maturation and degradation of proteins that traverse the secretory pathway in the living cell. Protein maturation is a highly assisted process enlisting the help of many cellular factors. We are particularly interested in understanding the role of co-translational folding and modifications that occur in the endoplasmic reticulum, and the involvement of molecular chaperones in these processes. The cell also possesses a quality control system that helps to ensure that only properly folded and assembled proteins are generated. Proteins that are unable to reach their native conformation are targeted for destruction. As our knowledge of protein maturation and quality control increases, it has become clear that a number of common human genetic diseases involve protein maturation defects including cystic fibrosis, albinism, melanoma and heart disease. Current model proteins that our laboratory studies include: tyrosinase, the key protein in melanin synthesis or cellular pigmentation; and the flu viral glycoprotein, hemagglutinin. We employ a variety of cell biololgical, biochemical, and molecular biological approaches to study the maturation and degradation of membrane glycoproteins using cell-free asssays, isolated organelles and live cells.

Figure 1: Model of the maturation and degradation pathway of the membrane glycoprotein, tyrosinase.
Representative Publications

Wang N, Hebert DN. (2006) Tyrosinase maturation through the mammalian secretory pathway: bringing color to life. Pigment Cell Research. February; 19 (1): 3-18.

Cormier JH, Pearse BR, Hebert DN. (2005) Yos9p: a sweet-toothed bouncer of the secretory pathway. Mol Cell. 19(6):717-9.

Wang N, Daniels R, Hebert DN. (2005) The cotranslational maturation of the type I membrane glycoprotein tyrosinase: the heat shock protein 70 system hands off to the lectin-based chaperone system. Mol Biol Cell. 16(8):3740-52.

Hebert DN, Garman SC, Molinari M. The glycan code of the endoplasmic reticulum: asparagine-linked carbohydrates as protein maturation and quality-control tags. Trends Cell Biol. 2005 Jul;15(7):364-70. Review.

Daniels R, Svedine S, Hebert DN. N-linked carbohydrates act as lumenal maturation and quality control protein tags. Cell Biochem Biophys. 2004;41(1):113-38.

Svedine S, Wang T, Halaban R, Hebert DN. Carbohydrates act as sorting determinants in ER-associated degradation of tyrosinase. J Cell Sci. 2004 Jun 15;117(Pt 14):2937-49. Epub 2004 May 25.

Francis E, Wang N, Parag H, Halaban R, Hebert DN. Tyrosinase maturation and oligomerization in the endoplasmic reticulum require a melanocyte-specific factor. J Biol Chem. 2003 Jul 11;278(28):25607-17. Epub 2003 Apr 30.

Wang T, Hebert DN. EDEM an ER quality control receptor. Nat Struct Biol. 2003 May;10(5):319-21. No abstract available.

Schnell DJ, Hebert DN. Protein translocons: multifunctional mediators of protein translocation across membranes. Cell. 2003 Feb 21;112(4):491-505. Review.

Daniels, R., B. Kurowski, A. E. Johnson and D. N. Hebert (2003) N-linked glycans direct the co-translational maturation of influenza hemagglutinin. Molecular Cell. 11:79-90.

Schnell, D. J. and D. N. Hebert (2003) Protein translocons: Multi-functional mediators of protein translocation across membranes. Cell 112:491-505

Wang, T. and D. N. Hebert (2003) EDEM, a quality control receptor. [News and Views], Nature Structure Biology 10(5):319-321.

Halaban, R., Hebert, D. N., and Fisher, D. E. (2003) Biology of melanocytes. In: I. M. Freedberg, A. Z. Eisen, K. Wolff, F. K. Austen, L. A. Goldsmith, and S. I. Katz (eds.), Dermatology In General Medicine, 6th edition, Vol. I, pp. 127-148. New York, NY: McGraw Hill Medical Publishing.

Hebert, D. N. (2003) Totally Sweet. [book review] Nat. Struct. Biol. 10(6):412

Francis, E., N. Wang, H. Parag, R. Halaban and D. N. Hebert (2003) Tyrosinase maturation requires a melanocyte-specific factor. J. Biol. Chem. 11;278(28):25607-17.

Halaban, R., R. Patton, E. Cheng, S. Svedine, E. S. Trombetta, M. Wahl, S. Ariyan and D. N. Hebert (2002) Abnormal acidification of Melanoma cells induces tyrosinase retention in the early secretory pathway. J. Biol. Chem. 277: 14821-14828.

Halaban, R. E. Cheng and D. N. Hebert, (2002) Co-_Expression of Wild Type Tyrosinase Enhances Maturation of Temperature-Sensitive Tyrosinase Mutants, J. Invest. Derm., 119(2):481-488.

Francis, E., R. Daniels and D. N. Hebert (2002) Analysis of protein folding in vivo. In Current Protocols in Cell Biology, J. S. Bonifacino, M. Dasso, J. B. Harford, J. Lippincott-Schwartz, and K.M. Yamada, eds. NY: John Wiley & Sons Inc.

Újvári, A., R. Aron, T. Eisenhaure, E. Cheng, H. Parag, Y. Smicun, R. Halaban and D. N. Hebert (2001) Translation rate of tyrosinase determines its N-linked glycosylation level. J. Biol. Chem. 276:5924-5931.

Halaban, R., E. Cheng, S. Svedine, R. Aron, and D. N. Hebert, (2001) Proper folding and ER to golgi transport of tyrosinase are induced by its substrates, DOPA and tyrosine. J. Biol. Chem. in press. Dec 20, 2000.

Halaban, R., S. Svedine, E. Cheng, Y. Smicun, R. Aron and D. N. Hebert (2000) Endoplasmic reticulum retention is a common defect associated with tyrosinase-negative albinism. Proc. Natl. Acad. Sci. USA, 97:5889-5894.

Hebert, D. N. (1999) Protein unfolding, mitochondria offer a helping hand. Nature Structure Biology, 6:1084-1085.

Hebert, D. N., J.-X. Zhang and A. Helenius (1998) Protein folding and maturation in a cell-free system. Biochem. and Cell Biol., 76: 867-873.

Halaban, R., E. Chang, Y. Zhang, G. Moellmann, D. Henlon, M. Michalak, V. Setaluri and D.N. Hebert (1997) Aberrant retention of tyrosinase in the endoplasmic reticulum mediates accelerated degradation of the enzyme and contributes to the dedifferentiated phenotype of amelanotic melanoma cells, Proc. Natl. Acad. Sci. USA, 94: 6210-6215.

Hebert, D. N., B. Foellmer and A. Helenius (1997) Number and location of glycans determines substrate binding to calnexin and calreticulin J. Cell Biol. 139: 613-623.

Helenius, A., E. S. Trombetta, D.N. Hebert and J.F. Simons (1997) Calnexin, calreticulin and the folding of glycoproteins. Trends Cell Biology, 7: 193-200.

Hebert, D. N., B. Foellmer and A. Helenius (1996) Calnexin and calreticulin promote folding, delay oligomerization and suppress degradation of influenza hemagglutinin in microsomes. EMBO J. 12: 2961-2968.

Hebert, D. N., B. Foellmer and A. Helenius (1995) Glucose trimming and reglucosylation determine glycoprotein association with calnexin in the endoplasmic reticulum. Cell 81: 425-433.

Hebert, D.N., J.F. Simons, J.R. Peterson and A. Helenius (1995) Calnexin, calreticulin and BiP/Kar2p in protein folding. Cold Spring Harbor Symposia on Quantitative Biology, LX :405-415.