Professor, Biochemistry and Molecular Biology
Phone: 402-559-7557 (Office)
Ph.D., University of Florida, 1999
NIH Postdoctoral Fellow, Albert Einstein College of Medicine, 2003
Research Opportunities in my Lab:
Undergraduate summer research
Sorgen Lab Members: Hanjun Li, Gaelle Spagnol, Paul Sorgen, Andrew Trease and Li Zheng
Gap junctions are integral membrane proteins that enable the direct cytoplasmic exchange of ions and low-molecular-mass metabolites between adjacent cells. They provide a pathway for propagating and/or amplifying the signal transduction cascades triggered by cytokines, growth factors, and other cell signaling molecules involved in growth regulation and development. Dysfunctional intercellular communication via gap junctions has been implicated in causing many human diseases. The objective of my lab is to use a multi-disciplinary approach to identify the key intrinsic regulatory mechanisms that are responsible for Cx43 and Cx45 function. Our central hypothesis is that unique intermolecular interactions within the divergent carboxyl terminal (CT) domain of connexins affect gap junction regulation. More specifically, we hypothesize that in the failing heart, Cx43CT phosphorylation alters protein partner interactions leading to remodeling of Cx43 from the intercalated disc, and that dimerization of Cx45 CTs is, in part, responsible for the channel properties of Cx45 that distinguish it from Cx43 and for the dominant-negative effect of Cx45 in heteromeric channels with Cx43. It is well-known that the CT domain of connexins are key regulators of channel properties, and that dimerization of cytosolic domains are key regulators of ion channels. Our studies are significant because discovery of how interactions mediated by the CT domain can be modulated would open the door to strategies to ameliorate the pathological effects of altered connexin regulation in the failing heart. The following projects are ongoing in the lab to investigate this concept: 1) Define how tyrosine kinases downregulate Cx43 gap junction intercellular communication, 2) Determine how Cx43 phosphorylation alters protein partner interactions, and 3) Identify the importance and mechanism of Cx45CT dimerization.
Model of a Gap Junction Channel. Gap junctions are formed by the apposition of connexons from adjacent cells, where each connexon is formed by six connexin proteins The channel location has been indicated by the yellow circle.
Model of a Connexin with Cellular Partners. Connexins are tetraspan transmembrane domain proteins with intracellular N- and C-termini. There are 21 different connexin genes in the human genome. The abbreviations are as follows: NT, N-terminus; CL, cytoplasmic loop; CT, C-terminus; E1 and E2, extracellular loops 1 and 2; 1-4, transmembrane segments 1-4.
- Bahl, K., Xie, S., Spagnol, G., Sorgen, P.L., Naslavsky, N., and Caplan, S. (2016) EHD3 is Required for Tubular Recycling Endosome Stabilization and an Asparagine-Glutamic Acid Residue Pair within its EH Domain Dictates its Selective Binding to NPF Peptides. J. Biol. Chem. In Press
- Ambrosi, C., Ren, C., Spagnol, G., Cavin, G., Cone, A., Grintsevich, E., Sosinsky, G.E., and Sorgen, P.L.* (2016) Connexin43 forms Supramolecular Complexes through Non-Overlapping Binding Sites for Drebrin, Tubulin, and ZO-1. PLOS ONE. In Press.
- Li, H., Spagnol, G., Zheng, Li., Stauch, K.L., and Sorgen, P.L.* (2016) Regulation of Connexin43 function and expression by Tyrosine kinase 2. J. Biol. Chem. In Press.
- Spagnol, G., Al-Mugotir, M., Kopanic, J.L., Zach, S., Li, H., Trease, A.J., Grosely, R., and Sorgen, P.L.* (2016) Secondary structural analysis of the carboxyl terminal domain from different connexin isoforms. Biopolymers. 105:143-162.
- Spagnol, G., Kieken, F., Kopanic, J.L., Li, H., Zach, S., Stauch, K., Grosely, R., and Sorgen, P.L.* (2016) Structural studies of the Nedd4 WW domains and their selectivity for the Cx43 carboxyl-terminal domain. J. Biol. Chem. 291:7637-7650.
- Mir, R.A., Lovelace, J., Schafer, N.P., Simone, P.D., Kellezi, A., Kolar, C., Spagnol, G., Sorgen, P.L., Band, H., Band, V., and Borgstahl, G.E.O. (2016) Biophysical characterization and modeling of human Ecdysoneless (ECD) protein supports a scaffolding function. AIMS Biophysics. 3(1):195-208.
- Kopanic, J.L., Schlingmann, B., Koval, M., Lau, A.F., Sorgen, P.L., and Su, V.F. (2015) Degradation of gap junction connexins is regulated by the interaction with Cx43-interacting protein of 75 kDa (CIP75). Biochemical Journal. 466:571-585.
- Das, S., Majhi, P.D., Al-Mugotir, M.H., Rachagani, S., Sorgen, P.L., Batra, S.K., (2015) Membrane proximal ectodomain cleavage of MUC16 occurs in the acidifying Golgi/post-Golgi compartments. Scientific Reports. 5:9759.
±Image from paper chosen for journal cover of J. Biomolecular NMR, 2008.