Christian W. Zwieb, Ph.D. Habil

Ph.D. 1979, Habil 1987, Freie Universität, Berlin, Germany

Professor of Research, Department of Biochemsitry, MSC 7760
University of Texas Health Science Center at San Antonio
7703 Floyed Curl Drive
San Antonio, TX 78229-3900
tel: 210-567-0431

Affiliate Professor at University of Auburn, Auburn, Alabama

skype: czwieb
email: zwieb@uthscsa.edu



Signal Recognition Particle (SRP), tmRNP, RNA Sensors & Drug Delivery

My laboratory studies translational ribonucleoprotein particles (RNPs). Methods for determining RNP structure and function include comparative sequence analyses (see rnp.uthscsa.edu ), cloning and purification of the constituents, reconstitution of recombinant RNPs, site-directed mutagenesis, crosslinking, molecular modeling, as well as collaborative biophysical methods such as X-ray crystallography, NMR, and cryo-EM.

The signal recognition particle (SRP) plays an critical role in the membrane-targeting and secretion of proteins. SRP binds to the signals of secretory proteins as they emerge from the large ribosomal subunit and delays translation until the ribosome reaches the SRP receptor in the membrane. An SRP RNA molecule and six SRP proteins are indispensable components of the human SRP and contain features of functional importance. The purpose of the research is to better understand the contribution of these features to the assembly, structure, and function of the SRP. Two major topics are currently under investigation: (1) the roles of proteins SRP72 and SRP68, and (2) the structural and functional basis of the transient nature of signal peptide recognition.

The bacterial transfer-messenger RNP (tmRNP) recycles ribosomes that are trapped on broken mRNAs lacking stop codons and tags the partially-translated proteins for degradation. Components of the tmRNP are the tmRNA, small protein B (SmpB), and ribosomal protein S1. The investigations focus on (1) identifying the varied features of the tmRNAs across the phylogenetic spectrum, (2) resolving the structures of the free, protein-, and ribosome-bound E. coli tmRNP, and (3) identify regions which are important for tmRNP structure and function. A better understanding of this process is essential for counteracting the survival strategies of harmful bacteria and the development of new antibiotic targets.

Combinatorial RNA-based sensors and drug delivery. We exploit the vast potential of RNA molecules to interact with a wide variety of targets. Unlike conventional protein- and DNA-based detection systems, RNA reagents are quicker and more affordable to manufacture. They fulfill the urgent need for materials that instantaneously detect targets in technologically modest environments. When used as vehicles for drug delivery, the RNA materials are degraded in a controlled fashion leaving no trace. We foresee broad applications of our technology in field kits for the rapid identification of numerous targets in medicine, environmental monitoring, food safety, and bioterrorism prevention.


Projects

SRP

Proteins SRP68 and SRP72 bind to each other and to the SRP RNA. Our goal is to understand these interactions and their implications for SRP assembly, structure, and function. The SRP54 protein and the SRP RNA are in close proximity to the signal peptide, but how recognition occurs on the molecular level is unknown. Our goal is to trap the transiently-bound signal peptide and determine the structure of the complex. These studies are carried out in collaboration with Dr. Andy Hinck, University of Texas, Health Science Center San Antonio, Texas, U.S.A.

tmRNP

We use comparative sequence analyses to determine the structures of all tmRNAs across the phylogenetic spectrum in order to understand which regions are imporant and which may be species specific. (2) The tmRNA binds to SmpB and ribosomal protein S1 and changes its shape when bound to the ribosome. Our goal is to determine the structural differences between the varied functional stages of the E. coli tmRNP. (3) Certain tmRNP regions are redundant and others are essential for function. We determine the relative importance of each region in vitro and in vivo. These studies are carried out in collaboration with Dr. Jacek Wower, University of Auburn, Auburn, Alabama, U.S.A., as the Principal Investigator.

RNP databases

We develop tools to identify RNA genes and to generate and visualize RNA and protein alignments. Our focus is on SRPDB and tmRDB but we aim to expand into other RNPs. This work is carried out in collaboration with investigators in Denmark and Sweden. (See Nucleic Acids Res. (2006) 34:D163-D168)

RNA Sensors & Drug Delivery

We exploit the potential of RNA to sense a wide variety of targets. Long RNA chains designed to form RNA networks with hydrogel-like properties are synthesized and combined to achieve a multitude of detection and drug delivery needs.


Lay Summaries

SRP

Proteins carry signals as "zip codes" which are read by the signal recognition particle (SRP). Our work explains how SRP recognizes the signal and correctly delivers the proteins. To understand the medical implications of this work read about Günter Blobel's Nobel Prize in Medicine 1999.

tmRNP

This particle allows infectious bacteria to survive when challenged by antibiotics. We investigate how the bacterial escape can be blocked. See our highly accessed mini review.

RNP databases

We extract relevant data from the numerous available genome sequences and identify the important properties of the SRP and the tmRNP. More at rnp.uthscsa.edu.

RNA Sensors & Drug Delivery

RNA molecules recognize numerous targets and can be synthesized in the laboratory without needing animals for production. We are laying the technological foundation for the rapid identification of targets that threaten our lives in the areas of medicine, environmental monitoring, food safety, and bioterrorism prevention.


Selected Publications (recent citations listed first)

Zwieb, C., Nakao, Y., Nakashima, T., Yamaguchi, H., Goda, S., Andersen, E.S., Kakuta, Y. and Kimura, M. (2011) A three-dimensional model of RNase P RNA from the hyperthermophilic archaeon Pyrococcus horikoshii OT3. Biochem. Biophys. Res. Comm. [Abstract]

Bateman, A., Agrawal, S., Birney, E.,Bruford, E.A., Bujnicki, J.M., Cochrane, G., Cole, J.R, Dinger, M.E., Enright, A.E., Gardner, P.P., Gautheret, D., Griffiths-Jones,, S., Harrow. J., Herrero, J., Holmes, I.H., Hsien-Da Huang, H-D., Kelly, K.A., Kersey, P., Kozomara, A., Lowe, T.M., Marz, M., Moxon, S., Pruitt, K.D., Samuelsson, T., Stadler, P.F., Vilella, A.J., Vogel, J-H., Williams, K.P., Wright, M.W.3 and Zwieb, C. (2011) RNAcentral: a vision for an international database of RNA sequences. RNA. [Abstract]

Burks, J.M., Zwieb, C., Müller, F., Wower, I.K. and Wower, J. (2011) In silico analysis of IRES RNAs of foot-and-mouth disease virus and related picornaviruses. Arch. Virol. 156, 1737-1747. [Abstract]

Burks, J.M., Zwieb, C., Müller, F., Wower, I.K. and Wower, J. (2011) Comparative Structural Studies of Bovine Viral Diarrhea Virus IRES RNA. Virus Res. 160, 128-142. [Abstract]

Iakhiaeva, E., Iakhiaev, A. and Zwieb, C. (2010) Identification of amino acid residues in protein SRP72 required for binding to a kinked 5e motif of the human signal recognition particle RNA. BMC Mol. Biol., 11, 83 [Abstract]

Zwieb, C., and Adhya, S. (2009) Plasmid vectors for the analysis of protein-induced DNA bending. In: T. Moss (Ed.), DNA-protein Interactions: principles and protocols (third edition). Totowa, NJ: Humana Press Inc. Methods Mol. Biol. 543:547-562. [Abstract]

Wower, J., Zwieb, C., and Wower, I.K. (2009) Escherichia coli tmRNA lacking pseudoknot 1 tags truncated proteins in vivo and in vitro. RNA, 15, 128-137. [Abstract]

Ilangovan, U., Bhuiyan, S.H., Hinck, C.S., Hoyle, J., Pakhomova, O.N., Zwieb, C. and Hinck, A.P. (2008) A. fulgidus SRP54 M-domain. J. Biomol. NMR. 4, 241-248. [Abstract]

Wower, J., Wower, I.K., and Zwieb, C. (2008) Making the jump: New insights into the mechanism of trans-translation (Minireview). J. Biol. 7, 17. [Abstract]

Iakhiaeva, E., Wower, J., Wower, I.K. and Zwieb, C. (2008) The 5e motif of eukaryotic signal recognition particle RNA contains a conserved adenosine for the binding of SRP72. RNA, 14, 1143-1153. [Abstract]

Yin, J, Iakhiaeva, E., Menichelli, E., and Zwieb, C. (2007) Identification of the RNA binding regions of SRP68/72 and SRP72 by systematic mutagenesis of human SRP RNA. RNA Biol. 4, 154-159. [Abstract]

Iakhiaeva, E., and Zwieb, C. (2007) Characterization of protein-RNA complexes using QIAGEN Ni NTA paramagnetic agarose beads. QIAGEN News 2007 e15. [Article]

Andersen ES, Lind-Thomsen A, Knudsen B, Kristensen SE, Havgaard JH, Torarinsson E, Larsen N, Zwieb C, Sestoft P, Kjems J, and Gorodkin J. (2007) Semiautomated improvement of RNA alignments. RNA 13,1850-1869 [Abstract]

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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