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Kevin D. Raney, Ph.D.

Professor and Chair

Ph.D., Vanderbilt University, Nashville TN
B.A., Hendrix College, Conway, AR

 


 


DNA and RNA Metabolism

My lab is focused on protein-nucleic acid interactions.  DNA and RNA must be translocated (moved from place to place), unwound, unzipped, and hybridized in order to serve their functions of information storage and transfer.  The enzymes that perform these critical tasks are called helicases.  We study the biological and biochemical mechanisms of helicases.  For example, DNA replication, repair, and recombination are processes that require the activity of at least one helicase.  If specific helicases are mutated, DNA metabolism can be disrupted resulting in diseases such as cancer. The importance of RNA helicases is increasingly becoming recognized.  RNA transport, translation, and RNA interference are some of the processes that require the activity of at least one RNA helicase.  Many viruses encode their own DNA or RNA helicase; therefore these enzymes are potential targets for development of anti-viral drugs.  We are studying a DNA helicase from Bacteriophage T4 named Dda (for DNA-Dependent-ATPase).  Our goal in this project is to develop a detailed chemical and kinetic mechanism for DNA unwinding by this DNA helicase.  This work involves enzyme kinetics, structural determination by x-ray crystallography, and structure-function studies using mutagenesis.  A second project involves the Hepatitis C viral helicase NS3 (Non-Structural Protein 3).  NS3 is an RNA helicase that is also capable of unwinding DNA.  We are studying the mechanism of NS3 as well as its interactions with other HCV and cellular proteins with the goal being to recapitulate RNA replication in vitro using biological relevant substrates and proteins.  This information is being used for development of chemical and macromolecular approaches for inhibiting HCV replication in human cells.   Our research projects are currently expanding in two new directions:  1) development of new tools for studying and disrupting protein-protein interactions using a combination of chemical and macromolecular approaches coupled with protein mass spectrometry, and 2) development of single-molecule enzymology using highly fluorescent proteins and/or nanocrystals for studying individual proteins in solution and in cells.     

 

Selected Publications

Wang, X., Arnold, J.J., Uchida, A., Raney, K.D., and Cameron, C.E. (2009) "Phosphate release contributes to the rate-limiting step for unwinding by an RNA helicase" Nucleic Acids Res. epub ahead of press, doi: 10.1093/nar/gkp1118 [Abstract].

Blair, L. P., Tackett, A. J., and Raney, K. D. (2009) "Development and evaluation of a structural model for SF1B Helicase Dda" Biochemistry, 48, 2321-2329 [Abstract].

Jennings, T.A., Mackintosh, S.G., Harrison, M.K., Sikora, D., Sikora, B., Tackett, A.J., Cameron, C.E., and Raney, K.D., (2009) "NS3 helicase from the Hepatitis C Virus can function as a monomer or oligomer depending on enzyme and substrate concentrations" J. Biol. Chem. 284, 4806-4814 [Abstract].

Sikora, B.T., Chen, Y., Lichti, C.F., Harrison, M.K., Jennings, T. A., Tang, Y., Tackett, A. J., Jordan, J. B., Sakon, J., Cameron, C. E., and Raney, K. D. (2008) "Hepatitis C Virus NS3 helicase forms oligomeric structures that exhibit optimal DNA unwinding in vitro" J. Biol. Chem. 283, 11516-11525 [Abstract].

Jennings, T. A., Chen, Y., Huang, L., Jankowsky, E., Tackett, A. J., Cameron, C. E., and Raney, K. D. (2008)  "RNA unwinding activity of the Hepatitis C virus NS3 helicase is modulated by the NS5B polymerase"  Biochemistry, 47, 1126-1135 [Abstract].

Sikora, B., Eoff, R. L., Matson, S. W., and Raney, K. D. (2006) "DNA Unwinding by Escherichia Coli DNA helicase I (TraI) Provides Evidence for a Processive Monomeric Molecular Motor"  J. Biol. Chem., 281, 36110-36116 [Abstract].

Byrd, A. K., and Raney, K. D. (2006) "Displacement of a DNA Binding Protein by Dda Helicase" Nucleic Acids Research, 34, 3020-3029. [Abstract] 

Eoff, R. L., and Raney, K. D. (2006) "Intermediates revealed in the kinetic mechanism for DNA unwinding by a monomeric helicase" Nature. Structural and Mol. Biol. 13, 242-249. [Abstract]

Mackintosh, S. G., Lu, Z. L., Jordan, J. B., Harrison, M. K., Sikora, B., Sharma, S. D., Cameron, C. E., and Raney, K. D.* and Sakon, J.* (2006)  "Structural and Biological Identification of residues on the surface of NS3 helicase that are required for optimal replication of the Hepatitis C Virus"  J. Biol. Chem. 281, 3528-3535. [Abstract]

         *corresponding authors

Tang, Y., Chen, Y., Lichti, C. F., Hall, R. A., Raney, K. D. and Jennings, S. F. (2005) "CLPM: A Cross-Linked Peptide Mapping Algorithm for Mass Spectrometric Analysis"  BMC Bioinformatics, 6 (Suppl 2):S9, 1-14. [Abstract]

Huang, L., Hwang, J., Sharma, S.D., Hargittai, M.R., Chen, Y., Arnold, J.J., Raney, K.D., and Cameron, C.E. (2005) "Hepatitis C virus nonstructural protein 5A (NS5A) is an RNA-binding protein." J. Biol. Chem., 280, 36417-36428. [Abstract]

Byrd, A. K. and Raney, K. D. (2004) "Protein displacement by an assembly of helicase molecules aligned along single-stranded DNA" Nature Struct. Mol. Biol.,11, 531- 538. [Abstract]

Nanduri, B., Byrd, A. K., Eoff, R. L., Tackett, A. J., and Raney, K. D. (2002) "Pre-steady state DNA unwinding by bacteriophate T4 Dda helicase reveals a monomeric molecular motor" Proc. Natl. Acad. Sci. USA. 99, 14722-14727.[Abstract]

Morris, P. D. and Raney, K. D. (1999) "DNA Helicases Displace Streptavidin from Biotin-Labeled Oligonucleotides" Biochemistry, 38, 5164-5171. [Abstract]

 

E-mail:

RaneyKevinD@uams.edu

Office: 

(501) 686-5244   Biomedical Research Center 1 Room 405B

Labs:

(501) 686-7254 Biomedical Research Center 2 Rooms 421-2, 433-2, 419-2 and 417-2

FAX:

(501) 686-8169

 

 

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Department of Biochemistry and Molecular Biology
University of Arkansas for Medical Sciences
4301 W. Markham St., Slot 516
Little Rock, AR 72205