Ruprecht-Karls-Universitšt Heidelberg

Bernhard Dobberstein
Group Leader in the
DKFZ-ZMBH Alliance

ZMBH
Im Neuenheimer Feld 282
69120 Heidelberg, Germany
Tel.: + 49-6221 54 6825
Fax: +49-6221 54 5892
b.dobberstein@zmbh.uni-heidelberg.de


Protein insertion into the membrane of the endoplasmic reticulum


Proteins destined for export out of the cell or insertion into the membrane of the endoplasmic reticulum (ER) are synthesized as pre-proteins with an N-terminal signal sequence. This signal sequence mediates membrane insertion of these proteins and is then cleaved off by signal peptidase. Signal sequences comprise on average 15-25 amino acid residues and have a tripartite structure consisting of a hydrophobic region, flanked by an n-region and a c-region containing the signal peptidase cleavage site. Beyond these features, signal sequences are highly variable, both in length and in amino acid composition. Some signal sequences comprise more that 50 amino acid residues in length. Thus, the information within some signal sequences may account for more than just targeting to the ER membrane. We found that cleaved signal sequences can have functions as membrane integrated peptides, as peptides released from the membrane or as signal peptide fragments liberated from the membrane after processing by signal peptide peptidase (SPP). This adds a further facet to the general concept that bioactive peptides can be generated from macromolecules.
If interested in signal sequences, more information is available at: http://www.signalpeptide.de

Insertion of proteins into the membrane of the ER can occur cotranslationally or posttranslationally.  A particular “challenge” to the posttranslational  mode is the insertion of small hydrophobic proteins that span the membrane. We have identified an ATPase, Asna-1, that associates with certain tail anchored (TA) proteins and mediates their insertion into the ER membrane. We want to further characterise the Asna-1 mediated pathway of TA protein insertion.


 

Selected publications

Favaloro, V., Vilardi, F., Schlecht, R., Mayer, M.P. and Dobberstein, B. (2010). Asna1/TRC40-mediated membrane insertion of tail-anchored proteins. J. Cell Science 123 (Pt 9):1522-30.
Bozkurt, G., Stjepanovic, G., Vilardi. F., Amlacher, S., Wild, K., Bange, G., Favaloro, V., Rippe, K., Hurt, E., Dobberstein, B. and Sinning, I. (2009). Structural insights into tail-anchored protein binding and membrane insertion by Get3. PNAS 106:21131-21136.
Kelkar, A. and Dobberstein, B. (2009). Sec61beta, a subunit of the Sec61 protein translocation channel at the Endoplasmic Reticulum, is involved in the transport of Gurken to the plasma membrane. BMC Cell Biology 10:11 (doi: 10.1186/1471-2121-10-11).
Kapp, K., Schrempf, S., Lemberg. M.K. and Dobberstein, B. (2009). Post-targeting functions of signal peptides.  In: Protein Transport into the Endoplasmic Reticulum, Ed. R. Zimmermann, Landes Bioscience (Open access: http://www.landesbioscience.com/curie/chapter/4185/).
Dultz E., Hildenbeutel M., Martoglio B., Hochman J., Dobberstein B. and Kapp K. (2008). The signal peptide of the mouse mammary tumor virus rem protein is released from the ER membrane and accumulates in nucleoli. J Biol Chem. 283:9966-9976.
Favaloro, V., Spasic, M., Schwappach, B. and Dobberstein, B. (2008). Distinct targeting pathways for the membrane insertion of tail-anchored (TA) proteins. J. Cell Science 121: 1832-1840.
Schrempf, S., Froeschke, M., Giroglou, T., von Laer, D. and Dobberstein, B. (2007). Signal Peptide Requirements for Lymphocytic Choriomeningitis Virus Glycoprotein C Maturation and Virus Infectivity. Journal of Virology 81: 12515-12524.
Froeschke, M., Basler, M., Groettrup, M. and Dobberstein, B. (2003). Long-lived signal peptide of lymphocytic choriomeningitis virus glycoprotein pGP-C. J. Biol. Chem. 278: 41914-41920.
Martoglio, B. and Dobberstein, B. (1998). Signal sequences - more than just greasy peptides. TiCB 8: 410-415..