Clara Kielkopf
| Title | Associate Professor |
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| Institution | School of Medicine and Dentistry |
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| Department | Biochemistry and Biophysics |
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| Address | University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 712
Rochester NY 14642
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| Title | Associate Professor |
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| Institution | University of Rochester Medical Center |
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| Department | Cancer Center |
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| 1993 |
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| Hilldale Fellowship, University of Wisconsin-Madison | | 1994 |
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| 1997 | NSF Pre-Doctoral Fellowship | | 2002 |
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| Faculty Development Award, Johns Hopkins University | | 2003 |
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| Faculty Innovation Award, Johns Hopkins University | | 2004 |
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| Basil O'Connor Award | | 2004 |
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| Kimmel Scholar Award | | 2005 |
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| Prostate Cancer Foundation Award | | 2005 |
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| Faculty Research Initiative Award, Johns Hopkins University | | 2008 |
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| 'Hot' article and cover illustration for 'Biochemistry' journal | | 2009 |
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| Cover illustration for CSHL mRNA processing meeting abstract book | | 2010 |
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| Press release for 'Molecular Cell' article in URMC news | | 2011 |
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| Invited Chapter in Molecular Cloning 4th Ed. | | 2012 |
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| 'Hot' article for 'Biochemistry' journal |
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.
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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.
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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. J Mol Biol. 2012 Jan 27; 415(4):727-40.
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Gupta A, Kielkopf CL. Purification, crystallization and preliminary X-ray crystallographic analysis of a central domain of human splicing factor 1. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2011 Apr 1; 67(Pt 4):486-90.
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McLaughlin KJ, Jenkins JL, Kielkopf CL. Large favorable enthalpy changes drive specific RNA recognition by RNA recognition motif proteins. Biochemistry. 2011 Mar 8; 50(9):1429-31.
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Gupta A, Jenkins JL, Kielkopf CL. RNA induces conformational changes in the SF1/U2AF65 splicing factor complex. J Mol Biol. 2011 Feb 4; 405(5):1128-38.
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McLaughlin KJ, Strain-Damerell CM, Xie K, Brekasis D, Soares AS, Paget MS, Kielkopf CL. Structural basis for NADH/NAD+ redox sensing by a Rex family repressor. Mol Cell. 2010 May 28; 38(4):563-75.
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Jenkins JL, Shen H, Green MR, Kielkopf CL. Solution conformation and thermodynamic characteristics of RNA binding by the splicing factor U2AF65. J Biol Chem. 2008 Nov 28; 283(48):33641-9.
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Manceau V, Kielkopf CL, Sobel A, Maucuer A. Different requirements of the kinase and UHM domains of KIS for its nuclear localization and binding to splicing factors. J Mol Biol. 2008 Sep 5; 381(3):748-62.
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Lin Y, Kielkopf CL. X-ray structures of U2 snRNA-branchpoint duplexes containing conserved pseudouridines. Biochemistry. 2008 May 20; 47(20):5503-14.
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Kumar AO, Swenson MC, Benning MM, Kielkopf CL. Structure of the central RNA recognition motif of human TIA-1 at 1.95A resolution. Biochem Biophys Res Commun. 2008 Mar 21; 367(4):813-9.
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Swenson MC, Paranawithana SR, Miller PS, Kielkopf CL. Structure of a DNA repair substrate containing an alkyl interstrand cross-link at 1.65 A resolution. Biochemistry. 2007 Apr 17; 46(15):4545-53.
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Thickman KR, Sickmier EA, Kielkopf CL. Alternative conformations at the RNA-binding surface of the N-terminal U2AF(65) RNA recognition motif. J Mol Biol. 2007 Feb 23; 366(3):703-10.
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Sickmier EA, Frato KE, Shen H, Paranawithana SR, Green MR, Kielkopf CL. Structural basis for polypyrimidine tract recognition by the essential pre-mRNA splicing factor U2AF65. Mol Cell. 2006 Jul 7; 23(1):49-59.
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Sickmier EA, Frato KE, Kielkopf CL. Crystallization and preliminary X-ray analysis of a U2AF65 variant in complex with a polypyrimidine-tract analogue by use of protein engineering. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2006 May 1; 62(Pt 5):457-9.
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Manceau V, Swenson M, Le Caer JP, Sobel A, Kielkopf CL, Maucuer A. Major phosphorylation of SF1 on adjacent Ser-Pro motifs enhances interaction with U2AF65. FEBS J. 2006 Feb; 273(3):577-87.
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Thickman KR, Swenson MC, Kabogo JM, Gryczynski Z, Kielkopf CL. Multiple U2AF65 binding sites within SF3b155: thermodynamic and spectroscopic characterization of protein-protein interactions among pre-mRNA splicing factors. J Mol Biol. 2006 Feb 24; 356(3):664-83.
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Sickmier EA, Brekasis D, Paranawithana S, Bonanno JB, Paget MS, Burley SK, Kielkopf CL. X-ray structure of a Rex-family repressor/NADH complex insights into the mechanism of redox sensing. Structure. 2005 Jan; 13(1):43-54.
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Kielkopf CL, Lücke S, Green MR. U2AF homology motifs: protein recognition in the RRM world. Genes Dev. 2004 Jul 1; 18(13):1513-26.
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Kielkopf CL, Burley SK. X-ray structures of threonine aldolase complexes: structural basis of substrate recognition. Biochemistry. 2002 Oct 1; 41(39):11711-20.
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Kielkopf CL, Rodionova NA, Green MR, Burley SK. A novel peptide recognition mode revealed by the X-ray structure of a core U2AF35/U2AF65 heterodimer. Cell. 2001 Sep 7; 106(5):595-605.
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Kielkopf CL, Ding S, Kuhn P, Rees DC. Conformational flexibility of B-DNA at 0.74 A resolution: d(CCAGTACTGG)(2). J Mol Biol. 2000 Feb 25; 296(3):787-801.
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Kielkopf CL, Erkkila KE, Hudson BP, Barton JK, Rees DC. Structure of a photoactive rhodium complex intercalated into DNA. Nat Struct Biol. 2000 Feb; 7(2):117-21.
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Kielkopf CL, Bremer RE, White S, Szewczyk JW, Turner JM, Baird EE, Dervan PB, Rees DC. Structural effects of DNA sequence on T.A recognition by hydroxypyrrole/pyrrole pairs in the minor groove. J Mol Biol. 2000 Jan 21; 295(3):557-67.
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Kielkopf CL, White S, Szewczyk JW, Turner JM, Baird EE, Dervan PB, Rees DC. A structural basis for recognition of A.T and T.A base pairs in the minor groove of B-DNA. Science. 1998 Oct 2; 282(5386):111-5.
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Kielkopf CL, Baird EE, Dervan PB, Rees DC. Structural basis for G.C recognition in the DNA minor groove. Nat Struct Biol. 1998 Feb; 5(2):104-9.
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