Christian W. Zwieb Ph.D. 1979, Free University, Berlin, Germany
Proteins are essential to structure and function of the body. All proteins are synthesized in the cytosol and must be transported to the proper cellular compartments. Misplaced proteins cause hereditary diseases such as primary hyperoxaluria, high cholesterol, or cystic fibrosis. Critical in protein transport are signal sequences and a ribonucleoprotein complex called Signal Recognition Particle (SRP).
Although SRPs are present in all organisms, we are particularly interested in the composition, function, and evolution of the human SRP. We have cloned and expressed the human SRP RNA and the six SRP proteins. We are now in the process of determining how the proteins bind to the SRP RNA by observing nucleotide and amino acid residue changes that affect the structure and function of SRP. The SRP database and computer-aided 3-D molecular modeling help us to understand details of SRP-mediated protein targeting. Collaborations in the areas of NMR and X-Ray crystallography are aimed to resolve the SRP at the atomic level. Results from our studies will lead to a better understanding of how the SRP directs the protein traffic within human cells. This knowledge provides the intellectual framework for designing measures that control the expression of secreted proteins and confer protection against disease.
We also study tmRNA, a small bacterial RNA with properties of tRNA and mRNA united in a single molecule. tmRNA is part of a recently discovered process, called trans-translation, that regulates protein synthesis and expression.
Interactions between SRP RNA, SRP proteins, and the signal peptide. The association of human protein SRP54 with SRP RNA is dependent on protein SRP19. An SRP19-induced conformational change in the RNA appears to be critical. We study the structures of proteins and RNAs to determine details of their interaction and the mechanism of signal peptide recognition.
Expression and purification of SRP components. Biophysical experiments (crystallization, NMR, etc.) are made possible by the large-scale synthesis and expression of SRP RNA and proteins. Results from these experiments will ultimately lead to the determination of the molecular structure of the SRP. tmRNA. We are interested in the molecular details by which tmRNA recognizes the ribosome in trans-translation. These studies are carried out in collaboration with Dr. Jacek Wower, University of Auburn, Auburn, Alabama, U.S.A., as the Principal Investigator.Databases. SRPDB offers aligned sequences of the SRP RNA and the SRP proteins, phylogenetically ordered and annotated, as well as sample SRP RNA secondary structure diagrams, three-dimensional models, and search motifs. The tmRDB provides similar information about tmRNA and its associated proteins.
We ask "how do proteins cross membrane barriers and arrive at their proper destination?". The proteins carry signal sequences which act as "zip codes" that are recognized by the signal recognition particle (SRP), the "post office" of the cell. Our goal is to better understand the molecular mechanism by which SRP delivers the proteins to the correct place. For more information check out the News of October 11, 1999.
Iakhiaeva, E., Bhuiyan, S.H., Yin, J, and Zwieb, C. (2006) Protein SRP68 of human signal recognition particle: Identification of the RNA and SRP72-binding domains. Protein Science in press
Andersen, E.S., Rosenblad, M.A., Larsen,, N., Westergaard, J.C., Burks, J., Wower, I.K., Wower, J., Gorodkin, J., Samuelsson, T., and Zwieb, C. (2006) The tmRDB and SRPDB resources. Nucleic Acids Res. 34, D163-D168 [Abstract]
Burks, J., Zwieb, C., Müller, F., Wower, I.K., and Wower, J. (2005) Comparative three-dimensional modeling of tmRNA. BMC Mol. Biol., 6, 14 [Abstract]
Wower, I.K., Zwieb, C., and Wower, J. (2005) Transfer-messenger RNA unfolds as it transits the ribosome. RNA, 11, 668-673. [Abstract]
Zwieb, C., van Nues, R.W., Rosenblad, M.A., Brown, J., and Samuelsson, T. (2005) A nomenclature for all signal recognition particle RNAs. RNA, 11, 7-13. [Abstract]
Yin, J., Yang, C.H., and Zwieb, C. (2004) Two strategically-placed base pairs in helix 8 of mammalian signal recognition particle RNA are crucial for the SPR19-dependent binding of protein SRP54. RNA, 10, 574-580 [Abstract]
Alm Rosenblad, M., Zwieb, C., and Samuelsson, T. (2004) Identification and comparative analysis of components from the signal recognition particle in protozoa and fungi. BMC Genomics, 5, 5 [Abstract]
Zwieb, C. (2003) Signal recognition particle-mediated protein targeting. in: Recent Research Developments in Molecular Biology, Vol. 1, 205-224.
Huang, Q., Abdulrahman, S., Yin, J., and Zwieb, C. (2002) Interactions of Human Protein SRP54 with Signal Recognition Particle RNA: Modes of Signal Peptide Recognition. Biochemistry, 41, 11362-11371. [Abstract]
Wower, J. Zwieb, C., Hoffman, D.W., and Wower, I.K. (2002) SmpB: A protein that binds to tmRNA and tRNA. Biochemistry, 41, 8826-8836. [Abstract]
Pakhomova, O.P., Deep, S., Huang, Q., Zwieb, C., and Hinck, A.P. (2002) Solution Structure of Protein SRP19 of Archaeoglobus fulgidus Signal Recognition Particle. J. Mol. Biol. 317, 145-158. [Abstract]
Zwieb, C. and Eichler, J. (2001) Getting on target: The archaeal signal recognition particle. Archaea, 1, 27-34. available at http://archaea.ws/
Yin, J., Yang, C.H., and Zwieb, C. (2001) Assembly of human signal recognition particle (SRP): overlap of regions required for binding of protein SRP54 and assembly control. RNA, 7, 1389-1396. [Abstract]
Zwieb, C., Guven, S.A., Wower, I.K, and Wower, J. (2001) Three-dimensional folding of the tRNA-like domain of Escherichia coli tmRNA. Biochemistry, 40, 9587-9595. [Abstract]
Knudsen, B., Wower, J., Zwieb, C., and Gorodkin, J. (2001) tmRDB (tmRNA database). Nucleic Acids Res. 29, 171-172. [Abstract]
Wower, I.K., Zwieb, C., and Wower, J. (2000) Binding and cross-linking of tmRNA to ribosomal protein S1 on and off the Escherichia coli ribosome: implication of S1 in tmRNA function. EMBO J. 19, 6612-6621. [Abstract]
Bhuiyan, S., Gowda, K., Hotokezaka, H. & Zwieb, C. (2000) Assembly of archaeal signal recognition particle from recombinant components. Nucleic Acids Res. 28, 1365-1373. [Abstract]
Politz, J.C., Yarovoi,S. M., Kilroy, S., Gowda, K., Zwieb, C. and Pederson, T. (2000) Signal Recognition Particle Components in the Nucleolus. PNAS, 97, 55-60. [Abstract]
Zwieb, C., Müller, F., and Wower, J. (1999) Comparative three-dimensional modeling of tmRNA. Nucleic Acids Symposium Series, No. 41, 200-204.
Wower, J., Wower, I.K., and Zwieb, C. (1999) An extended hybrid model for translocation of tRNA and the structure of peptidyl transferase of the Escherichia coli ribosome. Nucleic Acids Symposium Series, No. 41, 187-191.
Clemons, W.J., Gowda, K., Black, S.D., Zwieb, C., and Ramakrishnan, V. (1999) Crystal structure of the conserved subdomain of human protein SRP54M at 2.1Å resolution: Evidence for the mechanism of signal peptide binding. JMB, 292, 697-705. [Abstract]
Zwieb C., Wower I., and Wower, J. (1999) Comparative Sequence Analysis of tmRNA. Nucleic Acids Res., 27, 2063-2071. [Abstract]
Walker K.P., Black,S.D., and Zwieb, C. (1995). Cooperative Assembly of Signal Recognition Particle RNA with Protein SRP19. Biochemistry, 34, 11989-11997.[Abstract]
Zwieb, C. (1992). Recognition of a tetranucleotide loop of signal recognition particle RNA by protein SRP19. J. Biol. Chem., 267:15650-15656.
Larsen N., and Zwieb C. (1991). SRP-RNA sequence alignment and secondary structure. Nucleic Acids Research, 19:209-215.
Zwieb C. (1989). Structure and function of signal recognition particle RNA. In: "Progress in Nucleic Acid Research and Molecular Biology", 37:207-234.
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