Steven R Goodman, PhD
- Professor of Biochemistry and Molecular Biology
Research Programs and Affiliations
- Biochemistry and Molecular Biology
- Biomedical Sciences Program
- Research Pillars
Education & Fellowships
- PhD: St. Louis University Medical School
- Proteomic assessment of sickle cell severity.
Research AbstractMy laboratory's research credits include the co-discovery of ankyrin; the discovery of nonerythroid spectrin; the demonstration of an essential role for spectrin in synaptic transmission, DNA repair, calcium entry from internal cellular stores; defining the role of spectrin as an E2/E3 ubiquitin conjugating/ligating enzyme; working out the defects in the spectrin membrane skeleton that lead to formation of the irreversibly sickled cell; development of an efficacious drug for treatment of Sickle Cell Disease; the first complete proteomic studies on the human erythrocyte proteome and the seminal studies on changes of this proteome in sickle cell disease.
My laboratory has demonstrated the existence of multiple spectrin isoforms; their structure; location; protein interactions; subunit sequences; and functions. Amongst these functions was the demonstration that spectrin in the nucleus serves as a scaffold for damaged DNA and repair enzymes; that the spectrin membrane skeletal protein 4.1 gates an endothelial cell store operated Ca2+ entry channel; and serves as an essential component of synaptic transmission.
We have extensively studied the basic protein interactions in the normal erythrocyte membrane skeleton. This led us to discover the spectrin binding protein called ankyrin and the identification of the actin-binding domain of spectrin. We also demonstrated that reversible oxidative damage to actin and diminished ubiquitination of spectrin leads to the irreversibly sickle cell (ISC).
We found that antioxidants that raise the reduced glutathione levels within RBCs can block the formation of dense ISCs in vitro and in vivo. A phase 2 human trial with n-acetyl-cysteine demonstrated a large reduction in sickle cell crisis rate with no major side effects. We then demonstrated that spectrin is a chimeric E2/E3 ubiquitin ligase, which can ubiquitinate itself and several other membrane skeletal proteins. Ubiquitination was found to regulate the dissociation of the spectrin-4.1-actin and spectrin-adducin-actin ternary complex, and this enzymatic activity is greatly diminished in sickle cell RBCs due to their altered redox status.
My laboratory has performed the first complete studies of the human RBC proteome and changes that occur in sickle cell disease. The proteomic studies led to the discovery of proteasomes in RBCs and the current RBC interactome map. In addition, it has shown that Sickle Cell RBC membranes have an adaptive response to oxidative stress where increased levels of proteins such as chaperonins, heat shock proteins, catalase, and peroxyredoxin are found; while lipid raft proteins are diminished. We are currently launching protein-profiling studies on RBCs, WBCs, and plasma to try to understand the wide variation in crises and clinical outcome for patients with homozygous sickle cell disease.
Kakhniashvili, D.G., Chaudhary, T., Zimmer. W.E., Bencsath, F.A., Jardine, I., and Goodman, S.R. 2001. Spectrin is an E2 Ubiquitin Conjugating Enzyme. Biochemistry. 40: 11630-11642
Pace, B. S., Shartava, A., Pack-Mabien, A Mulekar, M.., Ardia, A., and Goodman S.R., 2003. Effects of N-Acetylcysteine On Vaso-occlusive Episodes in Sickle Cell Disease. Am. J. Hematol. 73:26-32.
Kakhniashvili, D.G., Bulla, L.E. and Goodman, S.R. 2004. The Human Erythrocyte Proteome: Analysis by Ion Trap Tandem Mass Spectrometry. Molecular and Cellular Proteomics 3: 501-509.
Kakhniashvili, D.G. Griko, N.B., Bulla Jr.,L.A. and S. R. Goodman, 2005, The Proteomics of Sickle Cell Disease: Profiling of Erythrocyte Membrane Proteins by 2D-DIGE and Tandem Mass Spectrometry. Exper. Biol. Med. 230: 787-792.
Goodman, S.R., Kurdia, A., Ammann, L., Kakhniashvili, D., and Daescu, O. 2007. The Human Red Blood Cell Proteome and Interactome, Exper. Biol. & Med. 232: 1391-1408.
Electron Microscopy reconstruction of the yeast vacuolar ATPase. Ribbon models for individual protein subunits have been fit to the electron density.
From the lab of Stephan Wilkens, PhD.