We have discovered methods by which the secretory capacity of the cells most frequently used in biotechnology for the production of recombinant proteins can be increased several fold. This involves triggering the biogenesis of functional membranes of the secretory pathway. We accomplish this by expressing a mammalian protein whose principal function apppears to be the binding of ribosomes to the rough endoplasmic reticulum (ER). This singular event, the triggering of membrane biogenesis and secretion, mimics the terminal differentiation of secretory cells and tissues within the body. This enables us not only to study ways in which cells can be customized for commercial purposes, but to study how, for example, the resting B lymphocytic cells of the immune system are triggered into plasma cells in normal and disease states.
The fact that this process can also occur in yeast has developed into a new and exciting field of research using traditional genetic approaches, as well as the most modern of techniques: DNA arrays. In this case, we are in the process of identifying the hundreds of genes that are up-regulated during the process of membrane proliferation and the resulting secretory capacity increase in yeast cells. Our goal is to classify these upregulated genes into groups that may be under common control, and determine the "master genes" that regulate the cell's ability to secrete large amounts of proteins and peptides. We are confident that understanding this aspect of gene expression will enable us to engineer cells that are even more proficient at the production of proteins essential for therapeutic and pharmaceutical purposes.
The ribosome receptor, whose expression is key to triggering cells to secrete more protein, has a fascinating primary structure. The most striking feature is a stretch of 540 amino acids made up of a consensus decapeptide motif repeated 54 times in a row without interruption! We have shown that this unusual sequence binds ribosomes to the ER membrane, probably by interacting directly with the rRNA of the large subunit. One of our goals is to fully understand this unusual protein-RNA interaction. To this end we are using biochemical and structure-function analyses. Our ultimate goal is to obtain three-dimensional crystallographic data to fully characterize the interaction between these two essential cellular components: The ribosome and its receptor on the ER membrane.
Benyamini, P., Webster, P. and Meyer, D.I. Knockdown of p180 Eliminates the Terminal Differentiation of a Secretory Cell Line, Molecular Biology of the Cell, 2009; 20: 732-744.
Benyamini Payam, Webster Paul, Meyer David I Knockdown of p180 eliminates the terminal differentiation of a secretory cell line Molecular biology of the cell, 2009; 20(2): 732-44.
Block-Alper Laura, Webster Paul, Zhou Xianghong, Supeková Lubica, Wong Wing Hung, Schultz Peter G, Meyer David I IN02, a positive regulator of lipid biosynthesis, is essential for the formation of inducible membranes in yeast Molecular biology of the cell, 2002; 13(1): 40-51.
Block-Alper L, Webster P, Zhou X, Supekova L, Wong WH, Schultz PG and Meyer DI INO2, a positive regulator of lipid biosynthesis, is essential for the formation of inducible membranes in yeast, Mol. Biol. Cell, 2002; 13: 40-51.
Hyde M, Block-Alper L, Felix J, Webster P, Meyer DI Induction of secretory pathway components in yeast is associated with increased stability of their mRNA The Journal of cell biology. , 2002; 156(6): 993-1001.
Hyde Maureen, Block-Alper Laura, Felix Jahaira, Webster Paul, Meyer David I Induction of secretory pathway components in yeast is associated with increased stability of their mRNA The Journal of cell biology, 2002; 156(6): 993-1001.
Elsea S H, Clark I B, Juyal R C, Meyer D J, Meyer D I, Patel P I Assignment of beta-centractin (CTRN2) to human chromosome 2 bands q11.1-->q11.2 with somatic cell hybrids and in situ hybridization Cytogenetics and cell genetics, 1999; 84(1-2): 48-9.
Becker F, Block-Alper L, Nakamura G, Harada J, Wittrup KD and Meyer DI Expression of the 180 kDa ribosome receptor induces membrane proliferation and increased secretory activity in yeast,, J. Cell Biol, 1999; 146: 273-284.
Becker F, Block-Alper L, Nakamura G, Harada J, Wittrup K D, Meyer D I Expression of the 180-kD ribosome receptor induces membrane proliferation and increased secretory activity in yeast The Journal of cell biology, 1999; 146(2): 273-84.
Garces J A, Clark I B, Meyer D I, Vallee R B Interaction of the p62 subunit of dynactin with Arp1 and the cortical actin cytoskeleton Current biology : CB, 1999; 9(24): 1497-500.
Clark I B, Meyer D I Overexpression of normal and mutant Arp1alpha (centractin) differentially affects microtubule organization during mitosis and interphase Journal of cell science, 1999; 112 ( Pt 20)(24): 3507-18.
Savitz A J, Meyer D I Receptor-mediated ribosome binding to liposomes depends on lipid composition The Journal of biological chemistry, 1997; 272(20): 13140-5.
Bush G L, Meyer D I The refolding activity of the yeast heat shock proteins Ssa1 and Ssa2 defines their role in protein translocation The Journal of cell biology, 1996; 135(5): 1229-37.
Wanker E E, Sun Y, Savitz A J, Meyer D I Functional characterization of the 180-kD ribosome receptor in vivo The Journal of cell biology, 1995; 130(1): 29-39.
Mayinger P, Bankaitis V A, Meyer D I Sac1p mediates the adenosine triphosphate transport into yeast endoplasmic reticulum that is required for protein translocation The Journal of cell biology, 1995; 131(6 Pt 1): 1377-86.
Clark S W, Meyer D I ACT3: a putative centractin homologue in S. cerevisiae is required for proper orientation of the mitotic spindle The Journal of cell biology, 1994; 127(1): 129-38.
Schroer T A, Fyrberg E, Cooper J A, Waterston R H, Helfman D, Pollard T D, Meyer D I Actin-related protein nomenclature and classification The Journal of cell biology, 1994; 127(6 Pt 2): 1777-8.
Clark S W, Staub O, Clark I B, Holzbaur E L, Paschal B M, Vallee R B, Meyer D I Beta-centractin: characterization and distribution of a new member of the centractin family of actin-related proteins Molecular biology of the cell, 1994; 5(12): 1301-10.
Savitz A J, Meyer D I 180-kD ribosome receptor is essential for both ribosome binding and protein translocation The Journal of cell biology, 1993; 120(4): 853-63.
Mayinger P, Meyer D I An ATP transporter is required for protein translocation into the yeast endoplasmic reticulum The EMBO journal, 1993; 12(2): 659-66.
Paschal B M, Holzbaur E L, Pfister K K, Clark S, Meyer D I, Vallee R B Characterization of a 50-kDa polypeptide in cytoplasmic dynein preparations reveals a complex with p150GLUED and a novel actin The Journal of biological chemistry, 1993; 268(20): 15318-23.
Clark S W, Meyer D I Long lost cousins of actin Current biology : CB, 1993; 3(1): 54-5.
Clark S W, Meyer D I Centractin is an actin homologue associated with the centrosome Nature, 1992; 359(6392): 246-50.
Meyer D I Protein translocation into the endoplasmic reticulum: a light at the end of the tunnel Trends in cell biology, 1991; 1(6): 154-9.
Sanderson C M, Meyer D I Purification and functional characterization of membranes derived from the rough endoplasmic reticulum of Saccharomyces cerevisiae The Journal of biological chemistry, 1991; 266(20): 13423-30.
Sanderson C M, Savitz A J, Meyer D I Ribosome binding to endoplasmic reticulum Cell biophysics, 1991; 19(1-3): 17-23.
Bush G L, Tassin A M, FridÃ©n H, Meyer D I Secretion in yeast. Purification and in vitro translocation of chemical amounts of prepro-alpha-factor The Journal of biological chemistry, 1991; 266(21): 13811-4.
Savitz A J, Meyer D I Identification of a ribosome receptor in the rough endoplasmic reticulum Nature, 1990; 346(6284): 540-4.
Wiest D L, Burkhardt J K, Hester S, Hortsch M, Meyer D I, Argon Y Membrane biogenesis during B cell differentiation: most endoplasmic reticulum proteins are expressed coordinately The Journal of cell biology, 1990; 110(5): 1501-11.
Sanderson C M, Crowe J S, Meyer D I Protein retention in yeast rough endoplasmic reticulum: expression and assembly of human ribophorin I The Journal of cell biology, 1990; 111(6 Pt 2): 2861-70.
Meyer D I Receptor anti-idiotypes. Mimics--or gimmicks? Nature, 1990; 347(6292): 424-5.
Sanz P, Meyer D I Receptor-mediated binding of secretory protein precursors to endoplasmic reticulum membranes in yeast Biochemical Society transactions, 1990; 18(2): 143-6.
Sanz P, Meyer D I Secretion in yeast: preprotein binding to a membrane receptor and ATP-dependent translocation are sequential and separable events in vitro The Journal of cell biology, 1989; 108(6): 2101-6.
Hortsch M, Labeit S, Meyer D I Complete cDNA sequence coding for human docking protein Nucleic acids research, 1988; 16(1): 361-2.
Toyn J, Hibbs A R, Sanz P, Crowe J, Meyer D I In vivo and in vitro analysis of ptl1, a yeast ts mutant with a membrane-associated defect in protein translocation The EMBO journal, 1988; 7(13): 4347-53.
Meyer D I Preprotein conformation: the year's major theme in translocation studies Trends in biochemical sciences, 1988; 13(12): 471-4.
Hibbs A R, Meyer D I Secretion in yeast: in vitro analysis of the sec53 mutant The EMBO journal, 1988; 7(7): 2229-32.
Sanz P, Meyer D I Signal recognition particle (SRP) stabilizes the translocation-competent conformation of pre-secretory proteins The EMBO journal, 1988; 7(11): 3553-7.
Hortsch M, Meyer D I The human docking protein does not associate with the membrane of the rough endoplasmic reticulum via a signal or insertion sequence-mediated mechanism Biochemical and biophysical research communications, 1988; 150(1): 111-7.
Crimaudo C, Hortsch M, Gausepohl H, Meyer D I Human ribophorins I and II: the primary structure and membrane topology of two highly conserved rough endoplasmic reticulum-specific glycoproteins The EMBO journal, 1987; 6(1): 75-82.
Rothblatt J A, Webb J R, Ammerer G, Meyer D I Secretion in yeast: structural features influencing the post-translational translocation of prepro-alpha-factor in vitro The EMBO journal, 1987; 6(11): 3455-63.
Hortsch M, Avossa D, Meyer D I Characterization of secretory protein translocation: ribosome-membrane interaction in endoplasmic reticulum The Journal of cell biology, 1986; 103(1): 241-53.
Rothblatt J A, Meyer D I Secretion in yeast: reconstitution of the translocation and glycosylation of alpha-factor and invertase in a homologous cell-free system Cell, 1986; 44(4): 619-28.
Rothblatt J A, Meyer D I Secretion in yeast: translocation and glycosylation of prepro-alpha-factor in vitro can occur via an ATP-dependent post-translational mechanism The EMBO journal, 1986; 5(5): 1031-6.
Hortsch M, Meyer D I Transfer of secretory proteins through the membrane of the endoplasmic reticulum International review of cytology, 1986; 102(4): 215-42.
Ainger K J, Meyer D I Translocation of nascent secretory proteins across membranes can occur late in translation The EMBO journal, 1986; 5(5): 951-5.
Hortsch M, Avossa D, Meyer D I A structural and functional analysis of the docking protein. Characterization of active domains by proteolysis and specific antibodies The Journal of biological chemistry, 1985; 260(16): 9137-45.
Hortsch M, Meyer D I Immunochemical analysis of rough and smooth microsomes from rat liver. Segregation of docking protein in rough membranes European journal of biochemistry / FEBS, 1985; 150(3): 559-64.
Geering K, Meyer D I, Paccolat M P, KraehenbÃ¼hl J P, Rossier B C Membrane insertion of alpha- and beta-subunits of Na+,K+-ATPase The Journal of biological chemistry, 1985; 260(8): 5154-60.
Hortsch M, Griffiths G, Meyer D I Restriction of docking protein to the rough endoplasmic reticulum: immunocytochemical localization in rat liver European journal of cell biology, 1985; 38(2): 271-9.
Meyer D I Signal recognition particle (SRP) does not mediate a translational arrest of nascent secretory proteins in mammalian cell-free systems The EMBO journal, 1985; 4(8): 2031-3.
Rottier P, Armstrong J, Meyer D I Signal recognition particle-dependent insertion of coronavirus E1, an intracellular membrane glycoprotein The Journal of biological chemistry, 1985; 260(8): 4648-52.
Hortsch M, Meyer D I Pushing the signal hypothesis: what are the limits? Biology of the cell / under the auspices of the European Cell Biology Organization, 1984; 52(1 Pt A): 1-8.
Meyer D I, Dobberstein B Proteins mediating vectorial translocation: purification of the active domain of the endoplasmic reticulum docking protein Methods in enzymology, 1983; 96(1 Pt A): 692-700.
Meyer D I, Kvist S, Dobberstein B Assembly of membrane proteins Progress in clinical and biological research, 1982; 91(2): 23-35.
Meyer D I, Louvard D, Dobberstein B Characterization of molecules involved in protein translocation using a specific antibody The Journal of cell biology, 1982; 92(2): 579-83.
Meyer D I Proteins involved in the vectorial translocation of nascent peptides across membranes Progress in clinical and biological research, 1982; 85 Pt B(2): 125-33.
Meyer D I, Krause E, Dobberstein B Secretory protein translocation across membranes-the role of the "docking protein' Nature, 1982; 297(5868): 647-50.
Meyer D I, Dobberstein B A membrane component essential for vectorial translocation of nascent proteins across the endoplasmic reticulum: requirements for its extraction and reassociation with the membrane The Journal of cell biology, 1980; 87(2 Pt 1): 498-502.
Meyer D I, Dobberstein B Identification and characterization of a membrane component essential for the translocation of nascent proteins across the membrane of the endoplasmic reticulum The Journal of cell biology, 1980; 87(2 Pt 1): 503-8.
Meyer D I, Burger M M Isolation of a protein from the plasma membrane of adrenal medulla which binds to secretory vesicles The Journal of biological chemistry, 1979; 254(19): 9854-9.
Meyer D I, Burger M M The chromaffin granule surface: the presence of actin and the nature of its interaction with the membrane FEBS letters, 1979; 101(1): 129-33.
Meyer D I, Burger M M The chromaffin granule surface. Localization of carbohydrate on the cytoplasmic surface of an intracellular organelle Biochimica et biophysica acta, 1976; 443(3): 428-36.
Meyer D I, Barber A A Changes in microsomal enzyme activities during DAB carcinogenesis Chemico-biological interactions, 1973; 7(4): 231-40.
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