Rhett Kovall

Rhett A. Kovall , PhD

Professor

University of Cincinnati College of Medicine
Department of Molecular Genetics, Biochemistry and Microbiology
231 Albert Sabin Way MSB2201
Cincinnati, Ohio 45267-0524
Phone 513-558-4631
Email rhett.kovall@uc.edu

Professional Summary

My research interests involve understanding at the molecular level how extracellular receptor-ligand interactions are transduced into transcriptional outputs in the nucleus. Currently, research in my lab focuses on Notch signaling with a particular emphasis on the nuclear effector of the pathway - CSL. The Notch pathway is a highly conserved cell-to-cell signaling mechanism in metazoans that is essential for development and homeostasis. Aberrant Notch signaling underlies the pathogenesis of neural disorders, developmental defects, and cancer. CSL is a DNA-binding transcription factor that is required for both repression and activation of Notch target genes. The control of transcription by CSL is thought to occur through protein-protein interactions with specific coregulator proteins. In the absence of a signal, CSL binds corepressor proteins such as SHARP/MINT, KyoT2 and Hairless, which results in transcriptional silencing. Upon pathway activation, the intracellular domain of the receptor Notch translocates to the nucleus and binds CSL, which results in the displacement of corepressors from CSL and recruitment of the coactivator Mastermind. Formation of the CSL-Notch-Mastermind ternary complex is the switch that upregulates transcription from genes that are responsive to Notch signaling.

My laboratory uses x-ray crystallography to determine the structures of CSL-coregulator complexes, and other biophysical techniques, such as isothermal titration calorimetry (ITC), to characterize the affinity of these complexes. In parallel with these studies, we use cellular and biochemical methods to characterize and functionally validate our structural models. Ultimately, the goal of this research is to provide a molecular explanation for how transcription is regulated in the Notch pathway, which is critical for understanding Notch signaling in normal biological contexts and in diseased states such as cancer.

Education

B.A.: University of Colorado Boulder, Colorado, 1992 (Biochemistry)

Ph.D.: University of Oregon, Institute of Molecular Biology Eugene, Oregon, 1998 (Structural Biology & Biochemistry)

Post Doc: Columbia University New York, 2004

Research and Practice Interests

My research interests involve understanding at the molecular level how transcription is regulated in the Notch signaling pathway. The Notch pathway is a highly conserved cell-to-cell signaling mechanism in metazoans that is essential for embryonic development and tissue homeostasis. Aberrant Notch signaling underlies the pathogenesis of many human diseases, including congenital defects, cardiovascular disease, and cancer. Notch signaling ultimately results in changes in gene expression, which is regulated by CSL. CSL is a DNA-binding transcription factor that interacts with corepressors and coactivators to regulate transcriptional repression and activation, respectively, of Notch target genes.

My laboratory uses x-ray crystallography to determine the structures of CSL-coregulator complexes, and other biophysical techniques, such as isothermal titration calorimetry (ITC), to characterize the binding and affinity of these complexes. In parallel with these studies, we use cellular and biochemical methods to characterize and functionally validate our structural models. Ultimately, the goal of this research is to provide a molecular explanation for how transcription is regulated in the Notch pathway, which is critical for understanding Notch signaling in normal biological contexts and in diseased states such as cancer.

Research Support

Grant: #000076 Investigators:Kovall, Rhett 07-01-2006 -06-30-2007 Leukemia Research Foundation Structure-function of Notch-CSL Transcription Complexes: A Structural Basis for Developing Anti-Leukemia Drugs Role:PI $100,000.00 Closed Level:Private Non-Profit

Grant: #R01 CA120199 Investigators:Kovall, Rhett 09-30-2006 -12-31-2012 National Cancer Institute Structure and Function of CSL, the Transcriptional Regulator in the Notch Pathway Role:PI $1,193,684.00 Closed Level:Federal

Grant: #1278-10 Investigators:Kovall, Rhett 07-01-2009 -06-30-2014 Leukemia & Lymphoma Society Biophysical Characterization of Notch Pathway Transcription Complexes Role:PI $440,000.00 Active Level:Private Non-Profit

Grant: #MDA 135618 Investigators:Kovall, Rhett 07-01-2009 -06-30-2012 Muscular Dystrophy Association Analysis of Notch Transcriptional Mechanisms Required for Muscle Regeneration Role:PI $286,841.00 Closed Level:Private Non-Profit

Grant: #11PRE7070002 Investigators:Collins, Kelly; Kovall, Rhett 07-01-2011 -06-30-2013 American Heart Association - National Chapter Thermodynamic, in Vivo, and Structural Analysis of the Notch Pathway CSL-KyoT2 Corepressor Complex Role:Collaborator $46,000.00 Active Level:Private Non-Profit

Grant: #R01CA178974 Investigators:Kovall, Rhett 07-01-2013 -06-30-2018 National Cancer Institute Molecular mechanisms of transcriptional regulation in the Notch pathway Role:PI $322,001.00 Active Level:Federal

Grant: #13PRE15570002 Investigators:Collins, Kelly; Kovall, Rhett 07-01-2013 -06-30-2014 American Heart Association - National Chapter Structure and Function of the MINT/NCoR complex, a novel phosphorylation mechanism that regulates Notch signaling Role:Collaborator $26,000.00 Active Level:Private Non-Profit

Grant: #Notch Transcriptional Activation Subaward Investigators:Kovall, Rhett 03-01-2016 -02-28-2019 Florida Department of Health Lead optimization and preclinical evaluation of small molecule inhibitors of Notch Transcriptional Activation Role:PI $50,025.00 Active Level:Other State

Grant: #Small Molecule Inhibitors of NACK - 2017 Investigators:Kovall, Rhett 03-01-2017 -12-29-2020 Florida Department of Health Development of Small Molecule Inhibitors of NACK as Novel Cancer Therapeutic Agents Targeting the Notch Pathway Role:PI $33,350.00 Active Level:Other State

Grant: #139353 / MCB-1715822 Investigators:Kovall, Rhett 09-01-2017 -08-31-2018 National Science Foundation NSF/MCB-BSF: Quantitative analysis and modeling of Notch signaling using in vivo synthetic biology Role:PI $25,576.00 Active Level:Federal

Grant: #CCHMC Sub#313165 / R01GM079428 Investigators:Kovall, Rhett 09-17-2020 -07-31-2024 National Institute of General Medical Sciences Mechanisms of Homeodomain Transcription Factor Specificity Role:PI $99,366.00 Awarded Level:Federal

Publications

Peer Reviewed Publications

Yuan, Zhenyu; Friedmann, David R; Vanderwielen, Bradley D; Collins, Kelly J; Kovall, Rhett A (2012. ) Characterization of CSL (CBF-1, Su(H), Lag-1) Mutants Reveals Differences in Signaling Mediated by Notch1 and Notch2.The Journal of biological chemistry, , 287 (42 ) ,34904-16 More Information

Kovall, Rhett A (2012. ) In notch, one ANK repeat is not like the other.Structure (London, England : 1993), , 20 (2 ) ,202-4 More Information

Maier, Dieter; Kurth, Patricia; Schulz, Adriana; Russell, Andrew; Yuan, Zhenyu; Gruber, Kim; Kovall, Rhett A; Preiss, Anette (2011. ) Structural and functional analysis of the repressor complex in the Notch signaling pathway of Drosophila melanogaster.Molecular biology of the cell, , 22 (17 ) ,3242-52 More Information

VanderWielen, Bradley D; Yuan, Zhenyu; Friedmann, David R; Kovall, Rhett A (2011. ) Transcriptional repression in the Notch pathway: thermodynamic characterization of CSL-MINT (Msx2-interacting nuclear target protein) complexes.The Journal of biological chemistry, , 286 (17 ) ,14892-902 More Information

Bahassi, El Mustapha; Yin, Moying; Robbins, Susan B; Li, Ya-Qin; Conrady, Deborah G; Yuan, Zhenyu; Kovall, Rhett A; Herr, Andrew B; Stambrook, Peter J (2011. ) A human cancer-predisposing polymorphism in Cdc25A is embryonic lethal in the mouse and promotes ASK-1 mediated apoptosis.Cell division, , 6 (1 ) ,4 More Information

Kurth, Patricia; Preiss, Anette; Kovall, Rhett A; Maier, Dieter (2011. ) Molecular analysis of the notch repressor-complex in Drosophila: characterization of potential hairless binding sites on suppressor of hairless.PloS one, , 6 (11 ) ,e27986 More Information

Conrady, Deborah G; Flagler, Michael J; Friedmann, David R; Vander Wielen, Bradley D; Kovall, Rhett A; Weiss, Alison A; Herr, Andrew B (2010. ) Molecular basis of differential B-pentamer stability of Shiga toxins 1 and 2.PloS one, , 5 (12 ) ,e15153 More Information

Kovall, Rhett A; Blacklow, Stephen C (2010. ) Mechanistic insights into Notch receptor signaling from structural and biochemical studies.Current topics in developmental biology, , 92 ,31-71 More Information

Friedmann, David R; Kovall, Rhett A (2010. ) Thermodynamic and structural insights into CSL-DNA complexes.Protein science : a publication of the Protein Society, , 19 (1 ) ,34-46 More Information

Kovall, R A (2008. ) More complicated than it looks: assembly of Notch pathway transcription complexes.Oncogene, , 27 (38 ) ,5099-109 More Information

Friedmann, David R; Wilson, Jeffrey J; Kovall, Rhett A (2008. ) RAM-induced allostery facilitates assembly of a notch pathway active transcription complex.The Journal of biological chemistry, , 283 (21 ) ,14781-91 More Information

Kovall, Rhett A (2007. ) Structures of CSL, Notch and Mastermind proteins: piecing together an active transcription complex.Current opinion in structural biology, , 17 (1 ) ,117-27 More Information

Wilson, Jeffrey J; Kovall, Rhett A (2006. ) Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA.Cell, , 124 (5 ) ,985-96 More Information

Kovall, Rhett A; Hendrickson, Wayne A (2004. ) Crystal structure of the nuclear effector of Notch signaling, CSL, bound to DNA.The EMBO journal, , 23 (17 ) ,3441-51 More Information

Min, K Christopher; Kovall, Rhett A; Hendrickson, Wayne A (2003. ) Crystal structure of human alpha-tocopherol transfer protein bound to its ligand: implications for ataxia with vitamin E deficiency.Proceedings of the National Academy of Sciences of the United States of America, , 100 (25 ) ,14713-8 More Information

Kovall, R A; Matthews, B W (1999. ) Type II restriction endonucleases: structural, functional and evolutionary relationships. Current opinion in chemical biology, , 3 (5 ) ,578-83

Kovall, R A; Matthews, B W (1998. ) Structural, functional, and evolutionary relationships between lambda-exonuclease and the type II restriction endonucleases. Proceedings of the National Academy of Sciences of the United States of America, , 95 (14 ) ,7893-7

Rhett Kovall and Brian W. Matthews (1997. ) Toroidal Structure of Lambda-Exonuclease .Science, , 277 (5333 ) ,1824-1827

Collins, Kelly J; Yuan, Zhenyu; Kovall, Rhett A (2014. ) Structure and function of the CSL-KyoT2 corepressor complex: a negative regulator of notch signaling.Structure (London, England : 1993), , 22 (1 ) ,70-81 More Information

Su, Shengchang; Panmanee, Warunya; Wilson, Jeffrey J; Mahtani, Harry K; Li, Qian; Vanderwielen, Bradley D; Makris, Thomas M; Rogers, Melanie; McDaniel, Cameron; Lipscomb, John D; Irvin, Randall T; Schurr, Michael J; Lancaster, Jack R; Kovall, Rhett A; Hassett, Daniel J (2014. ) Catalase (KatA) plays a role in protection against anaerobic nitric oxide in Pseudomonas aeruginosa.PloS one, , 9 (3 ) ,e91813 More Information

Contreras, Ashley N; Yuan, Zhenyu; Kovall, Rhett A (2015. ) Thermodynamic binding analysis of Notch transcription complexes from D. melanogaster.Protein science : a publication of the Protein Society, , More Information

Torella, Rubben; Li, Jinghua; Kinrade, Eddie; Cerda-Moya, Gustavo; Contreras, Ashley N; Foy, Robert; Stojnic, Robert; Glen, Robert C; Kovall, Rhett A; Adryan, Boris; Bray, Sarah J (2014. ) A combination of computational and experimental approaches identifies DNA sequence constraints associated with target site binding specificity of the transcription factor CSL.Nucleic acids research, , 42 (16 ) ,10550-63 More Information

Yuan, Zhenyu; Praxenthaler, Heiko; Tabaja, Nassif; Torella, Rubben; Preiss, Anette; Maier, Dieter; Kovall, Rhett A (2016. ) Structure and Function of the Su(H)-Hairless Repressor Complex, the Major Antagonist of Notch Signaling in Drosophila melanogaster.PLoS biology, , 14 (7 ) ,e1002509 More Information

Oswald, Franz; Rodriguez, Patrick; Giaimo, Benedetto Daniele; Antonello, Zeus A; Mira, Laura; Mittler, Gerhard; Thiel, Verena N; Collins, Kelly J; Tabaja, Nassif; Cizelsky, Wiebke; Rothe, Melanie; Kühl, Susanne J; Kühl, Michael; Ferrante, Francesca; Hein, Kerstin; Kovall, Rhett A; Dominguez, Maria; Borggrefe, Tilman (2016. ) A phospho-dependent mechanism involving NCoR and KMT2D controls a permissive chromatin state at Notch target genes.Nucleic acids research, , 44 (10 ) ,4703-20 More Information

Tabaja, Nassif; Yuan, Zhenyu; Oswald, Franz; Kovall, Rhett A (2017. ) Structure-function analysis of RBPJ-interacting and tubulin-associated (RITA) reveals regions critical for repression of Notch target genes.The Journal of biological chemistry, , More Information

Kovall, Rhett A; Gebelein, Brian; Sprinzak, David; Kopan, Raphael (2017. ) The Canonical Notch Signaling Pathway: Structural and Biochemical Insights into Shape, Sugar, and Force.Developmental cell, , 41 (3 ) ,228-241 More Information

Xu, Tao; Park, Sung-Soo; Giaimo, Benedetto Daniele; Hall, Daniel; Ferrante, Francesca; Ho, Diana M; Hori, Kazuya; Anhezini, Lucas; Ertl, Iris; Bartkuhn, Marek; Zhang, Honglai; Milon, Eléna; Ha, Kimberly; Conlon, Kevin P; Kuick, Rork; Govindarajoo, Brandon; Zhang, Yang; Sun, Yuqing; Dou, Yali; Basrur, Venkatesha; Elenitoba-Johnson, Kojo Sj; Nesvizhskii, Alexey I; Ceron, Julian; Lee, Cheng-Yu; Borggrefe, Tilman; Kovall, Rhett A; Rual, Jean-François (2017. ) RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1.The EMBO journal, , 36 (21 ) ,3232-3249 More Information

Nagel, Anja C; Auer, Jasmin S; Schulz, Adriana; Pfannstiel, Jens; Yuan, Zhenyu; Collins, Courtney E; Kovall, Rhett A; Preiss, Anette (2017. ) Phosphorylation of Suppressor of Hairless impedes its DNA-binding activity.Scientific reports, , 7 (1 ) ,11820 More Information

Miesfeld, Joel B; Moon, Myung-Soon; Riesenberg, Amy N; Contreras, Ashley N; Kovall, Rhett A; Brown, Nadean L (2018. ) Rbpj direct regulation of Atoh7 transcription in the embryonic mouse retina.Scientific reports, , 8 (1 ) ,10195 More Information

Oswald, Franz; Kovall, Rhett A (2018. ) CSL-Associated Corepressor and Coactivator Complexes.Advances in experimental medicine and biology, , 1066 ,279-295 More Information

Giaimo, Benedetto Daniele; Gagliani, Ellen K; Kovall, Rhett A; Borggrefe, Tilman (2021. ) Transcription Factor RBPJ as a Molecular Switch in Regulating the Notch Response.Advances in experimental medicine and biology, , 1287 ,9-30 More Information

Kobia, Francis M; Preusse, Kristina; Dai, Quanhui; Weaver, Nicholas; Hass, Matthew R; Chaturvedi, Praneet; Stein, Sarah J; Pear, Warren S; Yuan, Zhenyu; Kovall, Rhett A; Kuang, Yi; Eafergen, Natanel; Sprinzak, David; Gebelein, Brian; Brunskill, Eric W; Kopan, Raphael (2020. ) Notch dimerization and gene dosage are important for normal heart development, intestinal stem cell maintenance, and splenic marginal zone B-cell homeostasis during mite infestation.PLoS biology, , 18 (10 ) ,e3000850 More Information

Kuang, Yi; Golan, Ohad; Preusse, Kristina; Cain, Brittany; Christensen, Collin J; Salomone, Joseph; Campbell, Ian; Okwubido-Williams, FearGod V; Hass, Matthew R; Yuan, Zhenyu; Eafergan, Nathanel; Moberg, Kenneth H; Kovall, Rhett A; Kopan, Raphael; Sprinzak, David; Gebelein, Brian (2020. ) Enhancer architecture sensitizes cell specific responses to Notch gene dose via a bind and discard mechanism.eLife, , 9 , More Information

Thompson, Thomas B; Kovall, Rhett A (2019. ) Structural biology: Gaining atomic level insight into the biological function of macromolecules.Experimental biology and medicine (Maywood, N.J.), , 244 (17 ) ,1507-1509 More Information

Hall, Daniel P; Kovall, Rhett A (2019. ) Structurally conserved binding motifs of transcriptional regulators to notch nuclear effector CSL.Experimental biology and medicine (Maywood, N.J.), , 244 (17 ) ,1520-1529 More Information

Yuan, Zhenyu; VanderWielen, Bradley D; Giaimo, Benedetto Daniele; Pan, Leiling; Collins, Courtney E; Turkiewicz, Aleksandra; Hein, Kerstin; Oswald, Franz; Borggrefe, Tilman; Kovall, Rhett A (2019. ) Structural and Functional Studies of the RBPJ-SHARP Complex Reveal a Conserved Corepressor Binding Site.Cell reports, , 26 (4 ) ,845-854.e6 More Information

Hassett, Daniel J; Kovall, Rhett A; Schurr, Michael J; Kotagiri, Nalinikanth; Kumari, Harshita; Satish, Latha (2021. ) The Bactericidal Tandem Drug, AB569: How to Eradicate Antibiotic-Resistant Biofilm Pseudomonas aeruginosa in Multiple Disease Settings Including Cystic Fibrosis, Burns/Wounds and Urinary Tract Infections.Frontiers in microbiology, , 12 ,639362 More Information

Landor, Sebastian K J; Santio, Niina M; Eccleshall, William B; Paramonov, Valeriy M; Gagliani, Ellen K; Hall, Daniel; Jin, Shao-Bo; Dahlström, Käthe M; Salminen, Tiina A; Rivero-Müller, Adolfo; Lendahl, Urban; Kovall, Rhett A; Koskinen, Päivi J; Sahlgren, Cecilia PIM-induced phosphorylation of Notch3 promotes breast cancer tumorigenicity in a CSL-independent fashion.The Journal of biological chemistry, , 296 ,100593 More Information

Zhang, Xinghao; McGrath, Patrick S; Salomone, Joseph; Rahal, Mohamed; McCauley, Heather A; Schweitzer, Jamie; Kovall, Rhett; Gebelein, Brian; Wells, James M (2019. ) A Comprehensive Structure-Function Study of Neurogenin3 Disease-Causing Alleles during Human Pancreas and Intestinal Organoid Development.Developmental cell, , 50 (3 ) ,367-380.e7 More Information

Gomez-Lamarca, Maria J; Falo-Sanjuan, Julia; Stojnic, Robert; Abdul Rehman, Sohaib; Muresan, Leila; Jones, Matthew L; Pillidge, Zoe; Cerda-Moya, Gustavo; Yuan, Zhenyu; Baloul, Sarah; Valenti, Phillippe; Bystricky, Kerstin; Payre, Francois; O'Holleran, Kevin; Kovall, Rhett; Bray, Sarah J (2018. ) Activation of the Notch Signaling Pathway In Vivo Elicits Changes in CSL Nuclear Dynamics.Developmental cell, , 44 (5 ) ,611-623.e7 More Information

Greenwald, Iva; Kovall, Rhett (2013. ) Notch signaling: genetics and structure.WormBook : the online review of C. elegans biology, , 1-28 More Information

Kovall, R; Matthews, B W (1997. ) Toroidal structure of lambda-exonuclease.Science (New York, N.Y.), , 277 (5333 ) ,1824-7 More Information

Courses Taught

-GNTD-7001 MOL CELL BIOLOGY Level:Graduate

-MG-6005 MECH SIG TRANS Level:Graduate

-MG-7004 PROTEINS:STRUC FUNC Level:Graduate

-MG-8010 ADV MACROMOLE STRUC Level:Graduate

Contact Information

Academic - University of Cincinnati College of Medicine
Department of Molecular Genetics, Biochemistry and Microbiology
Cincinnati  Ohio, 45267-0524
Phone: 513-558-4631
rhett.kovall@uc.edu