Francis J Castellino, PhD

Director, Kleiderer-Pezold Professor of Biochemistry

Francis J - Castellino, PhD

Contact Info:

Phone: 574-631-8996


Faculty Spotlight: Community Research Collaboration



1996–present Director, WM Keck Center for Transgene Research, University of Notre Dame
1983–present Kleiderer/Pezold Professor of Biochemistry, University of Notre Dame
1979–2002 Dean, College of Science, University of Notre Dame
1977–1983 Professor, University of Notre Dame
1974–1977 Associate Professor, University of Notre Dame
1970–1974 Assistant Professor, University of Notre Dame
1968–1970 NIH Postdoctoral Fellow, Duke University
1968 Ph.D. Biochemistry, University of Iowa
1964 B.S. University of Scranton

Honors & Awards

2014 Distinguished alumnus, University of Iowa Carver School of Medicine
2008  Wyeth-ISPF Research Prize
2006 Fellow of the Reilly Center for Science, Technology, and Values
2003 Annual Faculty Award, University of Notre Dame
2001 Elected Fellow of the American Heart Association and the Council on Arteriosclerosis, Thrombosis, and Vascular Biology

Research Interests

My laboratory studies the structure, function and activation of proteins that participate in blood coagulation and blood clot dissolution. The in vivo mechanisms of the roles of these proteins in these processes are being addressed through in vivo targeted gene-replacement approaches and corresponding in vitro structure-function studies on these genes and proteins are being studied by the most modern biophysical techniques, e.g., X-ray crystallography, NMR, etc. Most of these proteins exist in an inactive state in plasma and thus must be activated to enzymes to exhibit their functional properties. The molecular events involved in the activation and analysis of the concomitant structural changes that occur in the protein are investigated by modern biochemical techniques. Major tools of the laboratory involve cloning, mutagenesis and expression of variant recombinant proteins and individual protein domains, immunochemical studies of the proteins, as well as physical and chemical analysis of their solution structures. The properties of the proteins are then related to their functions. One project receiving attention involves the structure-function relationships of small gamma-carboxyglutamic acid (Gla)-containing peptides from marine cone snails that target the brain NMDA receptor. These peptides inhibit the flow of calcium into neuronal cells, this latter event being responsible for the neuropathology associated with stroke, epilepsy, Alzheimer's Disease, ALS, etc. The biochemical, pharmacological and neurobiological mechanisms of the actions of these peptides are under study. Peptide synthesis, receptor binding, molecular biological and electrophysiological tools are currently employed in this work. To determine the biological functions of genes encoding coagulation and clot-dissolving proteins in hemostasis, cancer, inflammation, bacterial invasion, wound healing, embryonic implantation and development, metastases, and atherosclerosis, gene deletion and other gene targeting experiments are being performed in mice, in conjunction with phenotyping of these animals. Such studies are expected to provide important information on the development and progression of these disease states.

Recent Papers

Yuan Y, Ayinuola YA, Singh D, Ayinuola O, Mayfield JA, Quek A, Whisstock JC, Law RHP, Lee SW, Ploplis VA, Castellino FJ.  Solution structural model of the complex of the binding regions of human plasminogen with its M-protein receptor from Streptococcus pyogenes. J Struct Biol. 2019 Jul 10. pii: S1047-8477(19)30154-6. doi: 10.1016/j.jsb.2019.07.005. [Epub ahead of print] PMID: 31301349

Walsh M, Moore EE, Moore H, Thomas S, Lune SV, Zimmer D, Dynako J, Hake D, Crowell Z, McCauley R, Larson EE, Miller M, Pohlman T, Achneck HE, Martin P, Nielsen N, Shariff F, Ploplis VA, Castellino FJ. Use of Viscoelastography in Malignancy-Associated Coagulopathy and Thrombosis: A Review. Semin Thromb Hemost. 2019 Jun;45(4):354-372. doi: 10.1055/s-0039-1688497. Epub 2019 May 20. PMID: 31108555

Ly D, Donahue D, Walker MJ, Ploplis VA, McArthur JD, Ranson M, Castellino FJ, Sanderson-Smith ML. Characterizing the role of tissue-type plasminogen activator in a mouse model of Group A streptococcal infection. Microbes Infect. 2019 Apr 19. pii: S1286-4579(19)30051-6. doi: 10.1016/j.micinf.2019.04.004. [Epub ahead of print] PMID: 31009808

Qiu C, Yuan Y, Liang Z, Lee SW, Ploplis VA, Castellino FJ. Variations in the secondary structures of PAM proteins influence their binding affinities to human plasminogen. J Struct Biol. 2019 May 1;206(2):193-203. doi: 10.1016/j.jsb.2019.03.003. Epub 2019 Mar 14. PMID: 30880082

Qiu C, Yuan Y, Zajicek J, Liang Z, Balsara RD, Brito-Robionson T, Lee SW, Ploplis VA, Castellino FJ. Contributions of different modules of the plasminogen-binding Streptococcus pyogenes M-protein that mediate its functional dimerization. J Struct Biol. 2018 Nov;204(2):151-164. doi: 10.1016/j.jsb.2018.07.017. Epub 2018 Jul 30.PMID: 30071314


Flaherty RA, Donahue DL, Carothers KE, Ross JN, Ploplis VA, Castellino FJ, Lee SW.

Neutralization of Streptolysin S-Dependent and Independent Inflammatory Cytokine IL-1β Activity Reduces Pathology During Early Group A Streptococcal Skin Infection. Front Cell Infect Microbiol. 2018 Jul 3;8:211. doi: 10.3389/fcimb.2018.00211. eCollection 2018.PMID: 30018884


Miyajima C, Iwaki T, Umemura K, Ploplis VA, Castellino FJ. Characterization of Atherosclerosis Formation in a Murine Model of Type IIa Human Familial Hypercholesterolemia.

Biomed Res Int. 2018 Jun 7;2018:1878964. doi: 10.1155/2018/1878964. eCollection 2018. PMID: 29977908


Liang Z, Stephens M, Ploplis VA, Lee SW, Castellino FJ .Draft Genome Sequences of Six Skin Isolates of Streptococcus pyogenes. Genome Announc. 2018 Jun 28;6(26). pii: e00592-18. doi: 10.1128/genomeA.00592-18.PMID: 29954901


Urano T, Castellino FJ, Suzuki Y. Regulation of plasminogen activation on cell surfaces and fibrin. J Thromb Haemost. 2018 May 20. doi: 10.1111/jth.14157. [Epub ahead of print] Review.PMID: 29779246


Miles LA, Baik N, Bai H, Makarenkova HP, Kiosses WB, Krajewski S, Castellino FJ, Valenzuela A, Varki NM, Mueller BM, Parmer RJ. The plasminogen receptor, Plg-RKT, is essential for mammary lobuloalveolar development and lactation. J Thromb Haemost. 2018 May;16(5):919-932. doi: 10.1111/jth.13988. Epub 2018 Apr 1.PMID: 29495105

Fields FR, Carothers KE, Balsara RD, Ploplis VA, Castellino FJ, Lee SW. Rational design of syn-safencin, a novel linear antimicrobial peptide derived from the circular bacteriocin safencin AS-48. J Antibiot (Tokyo). 2018 Feb 20. doi: 10.1038/s41429-018-0032-4. [Epub ahead of print] PMID: 29463889


Holmes A, Zhou N, Donahue DL, Balsara R, Castellino FJ. A deficiency of the GluN2C subunit of the N-methyl-D-aspartate receptor is neuroprotective in a mouse model of ischemic stroke. Biochem Biophys Res Commun. 2018 Jan 1;495(1):136-144. doi: 10.1016/j.bbrc.2017.10.171. Epub 2017 Oct 31. PMID: 29101031


Yuan Y, Zajicek J, Qiu C, Chandrahas V, Lee SW, Ploplis VA, Castellino FJ. Conformationally organized lysine isosteres in Streptococcus pyogenes M protein mediate direct high-affinity binding to human plasminogen. J Biol Chem. 2017 Sep 8;292(36):15016-15027. doi: 10.1074/jbc.M117.794198. Epub 2017 Jul 19. PMID: 28724633


Bao YJ, Li Y, Liang Z, Agrahari G, Lee SW, Ploplis VA, Castellino FJ. Comparative pathogenomic characterization of a non-invasive serotype M71 strain Streptococcus pyogenes NS53 reveals incongruent phenotypic implications from distinct genotypic markers. Pathog Dis. 2017 Jul 31;75(5). doi: 10.1093/femspd/ftx056. PMID: 28520869

Gupta KK, Donahue DL, Sandoval-Cooper MJ, Castellino FJ, Ploplis VA. Plasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation. Sci Rep. 2017 Mar 23;7(1):365. doi: 10.1038/s41598-017-00418-y. PMID: 28336948

Glinton K, Beck J, Liang Z, Qiu C, Lee SW, Ploplis VA, Castellino FJ. Variable Region in Streptococcal M-Proteins Provides Stable Binding with Host Fibrinogen for Plasminogen-Mediated Bacterial Invasion. J Biol Chem. 2017 Mar 9. pii: jbc.M116.768937. doi: 10.1074/jbc.M116.768937. [Epub ahead of print] PMID: 28280245

Walsh M, Shreve J, Thomas S, Moore E, Moore H, Hake D, Pohlman T, Davis P, Ploplis V, Piscoya A, Wegner J, Bryant J, Crepinsek A, Lantry J, Sheppard F, Castellino F. Fibrinolysis in Trauma: "Myth," "Reality," or "Something in Between". Semin Thromb Hemost. 2017 Mar;43(2):200-212. doi: 10.1055/s-0036-1597900. Epub 2017 Feb 20. PMID: 28219085

Bao YJ, Shapiro BJ, Lee SW, Ploplis VA, Castellino FJ. Phenotypic differentiation of Streptococcus pyogenes populations is induced by recombination-driven gene-specific sweeps. Sci Rep. 2016 Nov 8;6:36644. doi: 10.1038/srep36644. PMID: 27821851

Higashi DL, Biais N, Donahue DL, Mayfield JA, Tessier CR, Rodriguez K, Ashfeld BL, Luchetti J, Ploplis VA, Castellino FJ, Lee SW. Activation of band 3 mediates group A Streptococcus streptolysin S-based beta-haemolysis. Nat Microbiol. 2016 Jan 18;1:15004. doi: 10.1038/nmicrobiol.2015.4. PMID: 27571972

Bao YJ, Liang Z, Mayfield JA, McShan WM, Lee SW, Ploplis VA, Castellino FJ. Novel genomic rearrangements mediated by multiple genetic elements in Streptococcus pyogenes M23ND confer potential for evolutionary persistence. Microbiology. 2016 Aug;162(8):1346-59. doi: 10.1099/mic.0.000326. Epub 2016 Jun 21. PMID: 27329479

Gupta KK, Xu Z, Castellino FJ, Ploplis VA. Plasminogen activator inhibitor-1 stimulates macrophage activation through Toll-like Receptor-4. Biochem Biophys Res Commun. 2016 Aug 26;477(3):503-8. doi: 10.1016/j.bbrc.2016.06.065. Epub 2016 Jun 15. PMID: 27317488

Mamczak CN, Maloney M, Fritz B, Boyer B, Thomas S, Evans E, Ploplis VA, Castellino FJ, McCollester J, Walsh M. Thromboelastography in Orthopaedic Trauma Acute Pelvic Fracture Resuscitation: A Descriptive Pilot Study. J Orthop Trauma. 2016 Jun;30(6):299-305. doi: 10.1097/BOT.0000000000000537. PMID: 27206253

Yasui H, Donahue DL, Walsh M, Castellino FJ, Ploplis VA. Early coagulation events induce acute lung injury in a rat model of blunt traumatic brain injury. Am J Physiol Lung Cell Mol Physiol. 2016 Jul 1;311(1):L74-86. doi: 10.1152/ajplung.00429.2015. Epub 2016 May 17. PMID: 27190065

Bao YJ, Liang Z, Mayfield JA, Donahue DL, Carothers KE, Lee SW, Ploplis VA, Castellino FJ. Genomic Characterization of a Pattern D Streptococcus pyogenes emm53 Isolate Reveals a Genetic Rationale for Invasive Skin Tropicity. J Bacteriol. 2016 May 27;198(12):1712-24. doi: 10.1128/JB.01019-15. Print 2016 Jun 15. PMID: 27044623

Walsh M, Fritz S, Hake D, Son M, Greve S, Jbara M, Chitta S, Fritz B, Miller A, Bader MK, McCollester J, Binz S, Liew-Spilger A, Thomas S, Crepinsek A, Shariff F, Ploplis V, Castellino FJ. Targeted Thromboelastographic (TEG) Blood Component and Pharmacologic Hemostatic Therapy in Traumatic and Acquired Coagulopathy. Curr Drug Targets. 2016;17(8):954-70. PMID: 26960340

Agrahari G, Liang Z, Glinton K, Lee SW, Ploplis VA, Castellino FJ. Streptococcus pyogenes Employs Strain-dependent Mechanisms of C3b Inactivation to Inhibit Phagocytosis and Killing of Bacteria. J Biol Chem. 2016 Apr 22;291(17):9181-9. doi: 10.1074/jbc.M115.704221. Epub 2016 Mar 4. PMID: 26945067

Bao YJ, Liang Z, Mayfield JA, Lee SW, Ploplis VA, Castellino FJ. CovRS-Regulated Transcriptome Analysis of a Hypervirulent M23 Strain of Group A Streptococcus pyogenes Provides New Insights into Virulence Determinants. J Bacteriol. 2015 Oct;197(19):3191-205. doi: 10.1128/JB.00511-15. Epub 2015 Jul 27. PMID: 26216843

Chandrahas V, Glinton K, Liang Z, Donahue DL, Ploplis VA, Castellino FJ. Direct Host Plasminogen Binding to Bacterial Surface M-protein in Pattern D Strains of Streptococcus pyogenes Is Required for Activation by Its Natural Coinherited SK2b Protein. J Biol Chem. 2015 Jul 24;290(30):18833-42. doi: 10.1074/jbc.M115.655365. Epub 2015 Jun 12. PMID: 26070561

Gupta KK, Donahue DL, Sandoval-Cooper MJ, Castellino FJ, Ploplis VA. Abrogation of plasminogen activator inhibitor-1-vitronectin interaction ameliorates acute kidney injury in murine endotoxemia. PLoS One. 2015 Mar 23;10(3):e0120728. doi: 10.1371/journal.pone.0120728. eCollection 2015 Mar 23. PMID: 25799354