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William J. Lennarz, Ph.D.

lennarz Distinguished Professor Emeritus
Department of Biochemistry and Cell Biology

Institute for Cell and Developmental Biology

Life Sciences Building
Stony Brook University
Stony Brook, NY 11794-5215
Phone: 631-632-0846


  • Research Description
    Biosynthesis and catabolism of glycoproteins

    Our laboratory is interested in understanding several steps involved in glycoprotein synthesis, including N-glycosylation and protein folding, as well as the functions of the glycan chains. We are using yeast, a simple eukaryotic organism that can be genetically manipulated, to study glycoprotein assembly. More specifically, we are investigating the enzymatic processes of oligosaccharide addition and removal that occur in nascent polypeptides and misfolded glycoproteins, respectively (  fig.1 ). Evidence has been obtained that the enzyme PNGase associates with the proteasome during proteolysis of glycoproteins. In addition, PDI, the enzyme that catalyzes folding and disulfide bond formation in glycoproteins, is being studied (  fig.2 ). The crystal structure has been obtained and now we are studying the role of the various domains of this protein in its catalytic activity.

    Figure 1

    Figure 2

  • Publications
    1. Yan, Aixi, Lennarz, William J. Two Oligosaccharyl Transferase complexes exist in yeast and associate with two different translocons.  Glycobiology12:1407-15 (2005).
    2. Katiyar, Samiksha and Lennarz, William J. Intracellular localization of DNA repair protein, hHR23B, is cell cycle dependent.  Biochem Biophys Res Commun337:1296-300 (2005).
    3. Li, Guangtao, Zhou, Xiaoke, Zhao, Gang, Schindelin, Hermann and Lennarz, William J. Multiple modes of interaction of the deglycosylation enzyme, mPNGase, with the Proteasome.  Proc. Natl.  Acad. Sci. U.S.A. 102:15809-14 (2005).
    4. Tian, Geng, Xiang, Song, Lennarz, William J. and Schindelin, Hermann. The Crystal Structure of Yeast Protein Disulfide Isomerase Suggests Cooperativity between its Active Sites.  Cell124:61-73 (2006).
    5. Chavan, Manasi and Lennarz, William J. The Molecular Basis of Coupling of Translocation and N-Glycosylation.  Trends in Biochem. Sciences 31:17-20 (2006).
    6. Zhao, Gang, Zhou, Xiaoke, Wang, Liqun, Li, Guangtao, Kisker, Caroline, Lennarz, William J. and Schindelin, Hermann. Structure of the Mouse Peptide N-Glycanase-HR23 Complex Suggests Co-evolution of the Endoplasmic Reticulum-associated Degradation and DNA Repair Pathways.  J.  Biol Chem. 281:13751-61 (2006).
    7. Guangtao Li, Gang Zhao, Xiaoke Zhou, Hermann Schindelin and William J. Lennarz. The AAA ATPase p97 links Peptide N-glycanase to the ER associated E3 ligase autocrine motility factor receptor.  Proc. Natl. Acad. Sci. U.S.A. 103:8348-53 (2006).
    8. Zhou, Xiaoke, Zhao, Gang, Wang, Liqun, Li, Guangtao, Lennarz, William J. and Schindelin, Hermann. The Crystal Structure of the C-terminal Domain of Mouse Peptide:N-Glycanase Identifies it as a Mannose-binding Module.  Proc. Natl. Acad. Sci. U.S.A. In press (2006).
    9. Chavan, Manasi, Chen, Zhiqiang, Li, Guangtao, Schindelin, Hermann, Lennarz, William J., Li, Huilin. Dimeric Organization of the Yeast Oligosaccharyl Transferase Complex.  Proc. Natl. Acad. Sci. U.S.A. 103:8947-52 (2006).
    10. Suzuki Tadashi, Hara I, Nakano M, Zhao G, Lennarz, William J, Schindelin, Hermann, Taniguchi N, Totani K, Matsuo I, Ito Y. Site Specific Binding of peptide:N-glycanase by N,N’-diacetylchitobiose-related compounds.  J. Biol Chem. 281:22152-22160 (2006).
  • Lab Members
    • Manasi Chavan
          Research Assistant Professor  One of my research interests is to understand the structural and functional details of the Oligosaccharyl transferase (OT) complex. The Oligosaccharyl Transferase complex catalyzes the N-glycosylation of nascent polypeptide chains in the lumen of the ER. This enzyme complex resides in the ER membrane and is composed of 9 subunits, all of which are transmembrane proteins. We have initiated electron microscopic analysis of the purified yeast OT complex, which has indicated that this complex may be dimeric in nature. We are now in the process of localizing each subunit within the overall structure of the OT complex.

      My other research interest is to understand the involvement of DAD1/Ost2p in apoptosis. Ost2p is an essential subunit of the yeast OT complex; DAD1 is its homolog in the mammalian OT complex. Prior results have indicated that DAD1 may be involved in the apoptotic cascade. Using the simpler yeast system, we plan to dissect this potential function of DAD1/Ost2p.

    • Guangtao Li
          Research Scientist We are working on how cells dispose of incorrectly folded glycoproteins. Earlier studies with mammalian cells have established that five cytoplasmic proteins can form a complex in vitro. This degradation complex may route the misfolded proteins to the proteasome. Currently we are studying the roles of its component in the ERAD degradation of glycoproteins.
    • Geng Tian
          Postdoctoral Research Fellow  Glycoprotein account for 40% of total cellular proteins and most of them utilize disulfide bonds to stabilize the three-dimensional structure. Protein disulfide isomerase (PDI) is the key ER resident enzyme responsible for the correct formation of disulfide bonds in secretory proteins. Our research interest is to understand how this enzyme catalyzes the disulfide formation, isomerization and eventually the protein folding with various structural biological approaches. After we obtain the crystal structure of yeast PDI, more detailed structural and biochemical studies will be carried out to further our understanding about this ancient but still fascinating enzyme.
    • Shivanjali Joshi
          Graduate Student I am investigating the role of Derlin family of proteins in the ER associated degradation (ERAD) pathway. The Derlin family of ER membrane proteins, comprised of Derlin-1, Derlin-2 and Derlin-3 in humans have been recently identified as a part of the ERAD machinery involved in dislocation of misfolded proteins from the ER to the cytosol. The mechanism of Derlin-mediated dislocation is poorly understood, although there is some speculation that these small, transmembrane spanning proteins may function as a protein export channel. To better understand the mechanism of Derlin mediated protein dislocation, we are utilizing the information obtained from global sequence alignment of various Derlin family members from different species to target highly conserved residues for site directed mutagenesis. The mutants would then be assessed for their functionality in the ERAD pathway, which will help us identify the crucial residues required for action of the Derlins.
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