Jay Groppe, Ph.D.

	Associate Professor Sciences Building, Room 226D Ph:   (214) 370-7203  Fax:  (214) 874-4538 jgroppe@bcd.tamhsc.edu Areas of expertise: Assembly of Bone Morphogenetic Protein (BMP) and Transforming Growth Factor-β (TGF-β) Signaling Complexes Inhibition of BMP Signaling by Secreted Antagonists (Ligand Traps) and Small Molecules (ATP Analog Kinase Inhibitors)

Research / Professional Interests

Over the last decade and a half, Dr. Groppe’s (pronounced GRAWP-ee’s) research has focused on the structure and function of Bone Morphogenetic Proteins (BMPs), signal ligands that play fundamental roles throughout embryonic development, including not only formation of bone but also tooth and craniofacial structures.  Initiated as an independent direction in the laboratory of Markus Affolter at the Biozentrum (Basel, Switzerland), this work spawned a collaboration with Senyon Choe, and as a visiting scientist in the Structural Biology Laboratory at the Salk Institute for Biological Studies (La Jolla, California), culminated in determination of crystal structures of BMP-7 trapped by the cystine knot antagonist Noggin (middle right) and complexed with type II receptor ECDs (below right).

As a Research Professor in the Department of Biochemistry at the UT Health Science Center at San Antonio, these studies were extended with Andrew Hinck to investigate the mechanism of cooperative assembly of signaling complexes by structurally related yet functionally distinct ligands, Transforming Growth Factor-βs (TGF-βs).  That effort led to the determination of the crystal structure of TGF-β3 (an obligate inducer of palatal fusion) in complex with both pairs of its receptors (left), revealing quite unexpectedly that the families of structurally related ligands and receptors assemble by strikingly different molecular mechanisms.

Because of their crucial roles in development and disease, rendering them important targets for therapeutic intervention, Noggin and related cystine knot antagonists such as Gremlin and Cerberus have remained the focus of ongoing protein structure-function studies.  A second major front in the study of the inhibition of BMP signaling has emerged through collaboration with Frederick Kaplan and Eileen Shore (University of Pennsylvania School of Medicine) who recently identified a mutant BMP receptor as the source of a severely disabling childhood disorder, Fibrodysplasia Ossificans Progressiva or FOP.  Results of a modeling study (left) based on the crystal structure of the TGF-β receptor kinase have lead to the hypothesis that a common histidine for arginine substitution introduces an aberrant pH-sensitive switch into the regulatory region of the BMP receptor kinase, allowing for ligand-independent activation of the receptor in FOP.  Crystal structures of kinase domains of wild-type and mutant receptors will be determined to identify precisely how this mutation, and others associated with atypical and variant forms of FOP, alter the three-dimensional structure of the protein and to provide models for rational design of ATP analog inhibitors targeted at the dysregulated receptor kinases.

Education

University of Basel, Switzerland

Postdoctoral Fellowship (1993-1999), Developmental Biology, Protein Chemistry

University of California, Santa Barbara, CA

Postdoctoral Fellowship (1992-1993), Bioorganic Chemistry
University of California, Santa Barbara, CA
Ph.D. (1991), Biochemistry - Molecular Biology
University of California, Santa Barbara, CA

B.A. (1980), Biochemistry - Molecular Biology

Career History

2007-present	Associate Professor, Department of Biomedical Sciences, Texas A&M Health Science Center Baylor College of Dentistry
2003-2007	Assistant Professor/Research, Department of Biochemistry, University of Texas Health Science Center at San Antonio
2000-2003	Visiting Scientist, Structural Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA
1993-1999	Postdoctoral Scientist, Department of Cell Biology, Biozentrum, University of Basel, Switzerland
1992-1993	Postdoctoral Scientist, Department of Chemistry, University of California at Santa Barbara
1987 (Jan-Apr)	Lecturer, Upper Division General Biochemistry, Department of Biological Sciences, University of California at Santa Barbara

Teaching Responsibilities

Biochemistry, Molecular and Cellular Biology (Dental, 6510)

Structural Basis of Signaling in Development (Graduate) 

Recent Grants

• Specificity Determinants and Binding Mechanism of Noggin, a Potent BMP Antagonist and Inhibitor of Vasculogenesis; American Heart Association/Texas Affiliate, Beginning Grant-in-Aid; 07/01/05-06/30/07; Role: PI
• Structural Basis of ACRV1 Dysregulation in Fibrodysplasia Ossificans Progressiva; The Center for Research in Fibrodysplasia Ossificans Progressiva and Related Disorders; University of Pennsylvania School of Medicine; 12/01/06-11/30/08; Role: PI

Peer-reviewed Publications

1. Ferguson, J., Groppe, J.C., and Reed, S.I. (1981).  Construction and characterization of three yeast-Escherichia coli shuttle vectors designed for rapid subcloning of yeast genes on small DNA fragments.  Gene 16:191-197.
2. Reed, S.I., Ferguson, J., and Groppe, J.C.  (1982).  Preliminary characterization of the transcriptional and translational products of the Saccharomyces cerevisiae cell division cycle gene CDC 28.  Mol. Cell. Biol. 2:412-425.
3. Groppe, J.C. and Morse, D.E. (1993).  Isolation of full-length RNA templates for reverse transcripton from tissues rich in RNase and proteoglycans.  Anal. Biochem. 210:337-343.
4. Groppe, J.C. and Morse, D.E. (1993).  Molluscan chymotrypsin-like protease: Structure, localization and substrate specificity.  Arch. Biochem. Biophys. 305:159-169.
5. Hansma, H.G., Sinsheimer, R.L., Groppe, J., Bruice, T.C., Elings, V., Gurley, Gl., Bezanilla, M., Mastrangelo, I.A., Hough, P.V.C. and Hansma, P.K. (1993).  Recent advances in atomic force microscopy of DNA.  Scanning 15:296-299.
6. He, G.-X., Browne, K.A., Groppe, J.C., Blasko, A., Mei, H-Y., and Bruice, T.C. (1993).  Microgonatropens and their interactions with DNA.  I. Synthesis of the tri-pyrrole peptides dienmicrogonatropen-a, -b,-c and characterization of their interactions with dsDNA.  J. Am. Chem. Soc. 115:7061-7071.
7. Bregnant, T.M., Groppe, J., and Little, R.D. (1994).  New class of DNA-cleaving agents based on trimethylenemethane.  J. Am. Chem. Soc. 116:3635-3636.
8. Affolter, M., Montagne, J., Walldorf, U., Groppe, J., Kloter, U., LaRosa, M. and Gehring, W.J. (1994).  The Drosophila SRF homolog is expressed in a subset of tracheal cells and maps within a genomic region required for trachel development.  Development 120:743-753.
9. Groppe, J.C. and Morse, D.E. (1995).  Sequence-independent detection of gene family homologs: Identification of a transcript encoding a molluscan serine protease homologous to the pancreatic enzymes of vertebrates.  Comp. Biochem. Physiol. 110B:75-82.
10. Degnan, B.M., Groppe, J.C., and Morse, D.E. (1995).  Chymotrypsin mRNA expression in digestive gland amoebocytes: Cell specification occurs prior to metamorphosis and gut morphogenesis in the gastropod, Haliotis rufescens.  Roux's Arch. Dev. Biol. 205:97-101.
11. Guillemin, K., Groppe, J., Ducker, K., Treisman, R., Hafen, E., Affolter, M. and Krasnow, M.A. (1996).  The pruned gene encodes the Drosophila serum response factor and regulates cytoplasmic outgrowth during terminal branching of the tracheal system. Development 122:1353-1362.
12. Montagne., J., Groppe, J., Guillemin, K., Krasnow, M.A., Gehring, W.J. and Affolter., M. (1996). The Drosophila serum response factor homolog is required for the formation of intervein tissue of the wing and is allelic to blistered.  Development 122:2589-2597.
13. Groppe, J., Rumpel, K., Economides, A.N., Stahl, N., Sebald, W. and Affolter, M.  (1998). Biochemical and biosphysical characterization of refolded Drosophila DPP, a homolog of bone morphogenetic proteins 2 and 4.  J. Biol. Chem. 273:29052-29065.
14. Nussbaumer, J., Halder, G., Groppe, J., Affolter, M. and Montagne, J. (2000).  Expression of the blistered/DSRF gene is controlled by different morphogens during drosophila trachea and wing develoment.  Mech Dev. 96:27-36.
15. Perrin, M.H., Fischer, W.H., Kunitake, K.S., Craig, A.G., Koerber, S.C., Cervini, L.A., Rivier, J.E., Groppe, J.C., Greenwald, J., Nielsen, S.M., and Vale, W.W. (2001).  Expression, purification, and characterization of a soluble form of the first extracullular domain of the human type 1 corticotropin releasing factor receptor.  J. Biol. Chem. 276:31528-31534.
16. Groppe, J., Greenwald., J. Wiater, E., Rodriguez-Leon, J., Economides, A., Kwiatkowski, W., Affolter., M., Vale, W.W., Izpisua-Belmont, J.C. and Choe, S. (2002).  Strucural basis of BMP signaling inhibition by Noggin, a novel cystine knot protein.  Nature 420:636-642.   [Commented on by Wrana, J. (2002). Structural biology: On the wings of inhibition.  Nature 420:613-614.]
17. Greenwald, J., Groppe, J., Gray, P., Wiater, E., Kwiatkowski, W., Vale, W.W., and Choe, S. (2003).  The BMP7/ActRII extracullular domain complex provides new insights into the cooperative nature of receptor assembly.  Mol. Cell. 11:605-617.  [Commented on by Sebald, W. and Mueller, T.D. (2002). The interaction of BMP-7 and ActR11 implicates a new mode of receptor assembly.  Trends Biochem Sci 28:518-521 and Sun, P.D. (2003).  Conserved in structure but diverse in recognition.  Structure 11:362-363.]
18. Groppe, J., Greenwald, J. Wiater, E., Rodriguez-Leon, J., Economides, A., Kwiatkowski., W. Baban, K., Affolter, M., Vale, W.W., Izpisua-Belmonte, J.C. and Choe, S. (2003).  Structural basis of BMP signaling inhibition by Noggin, a novel twelve-membered cystine knot protein.  J. Bone Joint Surg. Am 85-A, Supplement 3: 52-58.
19. Ilangoven, J., Ding, W., Zhong, Y., Wilson, C.L., Groppe, J.C., Trbovich, J.T., Zuniga, J., Demeler, B., Tang, Q., Gao, L., Mulder, K.M. and Hinck, A.P. (2005).  Structure and dynamics of the homodimeric dynein light chain km23.  J. Mol. Biol. 352:338-354.
20. Zuniga, J.E., *Groppe, J.C., Cui, Y., Hinck, C.S., Contreras-Shannon, V., Pakhomova, O.N., Yang, J., Tang, Y., Sun, L.-Z., and Hinck, A.P. (2005).  Assembly of TβRI:TβRII:TGFβ ternary complex in vitro with receptor extracellular domains is cooperative and isoform-dependent.  J. Mol. Bio.  354:1052-1068  (*equal first author, wrote paper).
21. Groppe, J.C., Shore, E.M. and Kaplan, F.S. (2007).  Functional modeling of the ACVR1 (R206H) mutation in FOP.  Clin. Orthop. Relat. Res. 462:87-92.
22. Kaplan, F.S., Groppe, J., Pignolo, R.J., and Shore, E.M.  Morphogen receptor genes and metamorphogenes: Skeleton keys to the metamorphosis.  Ann. NY Acad. Sci., epub ahead of print, 13 September 2007.
23. Groppe, J., Hinck, C.S., Samavarchi-Tehrani, P., Zubieta, C., Schuermann, J.P., Taylor, A.B., Schwarz, P.M., Wrana, J.L. and Hinck, A.P. Cooperative assembly of TGF-β superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding.  Mol. Cell., in press.