Research Bio
Up to half of human genetic diseases, including cancers and neuromuscular disorders, are associated with defects in splicing of pre-mRNA transcripts. Almost all human genes contain intervening, non-coding sequences that must be spliced from the pre-mRNA transcripts before translation into proteins. The majority of these are alternatively spliced to encode a number of protein variants depending on different cellular needs. My laboratory uses structural and biophysical techniques to understand how pre-mRNA splice sites are recognized in normal cells, and to suggest possible means for treating defective pre-mRNA splicing observed in human genetic diseases.
The major focus of the laboratory is the mechanism of 3' splice site recognition by complexes with the essential pre-mRNA splicing factor, U2 Auxiliary Factor (U2AF). Using biophysical methods including X-ray crystallography, fluorescence anisotropy, calorimetry, and surface plasmon resonance, we characterize the three-dimensional shapes and energetic forces that enable U2AF to recognize the pre-mRNA splice site. We recently determined a series of X-ray structures of U2AF a series of pre-mRNA splice site sequences. An immediate goal of the laboratory is to determine structures of higher order 3' splice site complexes, and the specific roles of phosphorylation and ATP hydrolysis during assembly of these structures. Knowledge of the key interactions between splicing factors and the pre-mRNA will assist the development of chemotherapeutics targeted at the level of pre-mRNA splicing.
Please visit our lab website for more information.
| 'Hot' article for 'Biochemistry' journal |
2012 |
| Invited Chapter in Molecular Cloning 4th Ed. |
2011 |
| Press release for 'Molecular Cell' article in URMC news |
2010 |
| Cover illustration for CSHL mRNA processing meeting abstract book |
2009 |
| 'Hot' article and cover illustration for 'Biochemistry' journal |
2008 |
| Prostate Cancer Foundation Award |
2005 |
| Faculty Research Initiative Award, Johns Hopkins University |
2005 |
| Basil O'Connor Award |
2004 |
| Kimmel Scholar Award |
2004 |
| Faculty Innovation Award, Johns Hopkins University |
2003 |
| Faculty Development Award, Johns Hopkins University |
2002 |
| NSF Pre-Doctoral Fellowship |
1994 - 1997 |
| Hilldale Fellowship, University of Wisconsin-Madison |
1993 |
2013 Apr 1
Jenkins JL, Agrawal AA, Gupta A, Green MR, Kielkopf CL. "U2AF65 adapts to diverse pre-mRNA splice sites through conformational selection of specific and promiscuous RNA recognition motifs." Nucleic acids research. 2013 Apr 1; 41(6):3859-73. Epub 2013 Feb 01. |
2013 Apr
Gleghorn ML, Gong C, Kielkopf CL, Maquat LE. "Staufen1 dimerizes through a conserved motif and a degenerate dsRNA-binding domain to promote mRNA decay." Nature structural & molecular biology. 2013 Apr 0; 20(4):515-24. Epub 2013 Mar 24. |
2012 Jul 3
Jenkins JL, Laird KM, Kielkopf CL. "A Broad range of conformations contribute to the solution ensemble of the essential splicing factor U2AF(65)." Biochemistry. 2012 Jul 3; 51(26):5223-5. Epub 2012 Jun 19. |
2012 Jan 27
Bauer WJ, Heath J, Jenkins JL, Kielkopf CL. "Three RNA recognition motifs participate in RNA recognition and structural organization by the pro-apoptotic factor TIA-1." Journal of molecular biology. 2012 Jan 27; 415(4):727-40. Epub 2011 Dec 02. |
2011 Apr 1
Gupta A, Kielkopf CL. "Purification, crystallization and preliminary X-ray crystallographic analysis of a central domain of human splicing factor 1." Acta crystallographica. Section F, Structural biology and
crystallization communications. 2011 Apr 1; 67(Pt 4):486-90. Epub 2011 Mar 25. |
