Drs. Orban and Mariuzza Awarded NIH R21 Funding

Drs. John Orban (Professor at the University of Maryland Institute of Bioscience and Biotechnology Research (IBBR) and Department of Chemistry and Biochemistry) and Roy Mariuzza (Professor at IBBR and Department of Cell Biology and Molecular Genetics) have recently been awarded R21 funding from the National Institutes of Health to study the process by which an immune cell receptor, the T-cell receptor (TCR) transduces signals across the plasma membrane upon binding a specific ligand, called peptide-MHC (pMHC), that is found on specialized antigen-presenting immune cells. Much is known about downstream T cell signaling and X-ray crystallography has been used to reveal the molecular basis for TCR recognition of foreign and self-antigens through TCR–peptide-MHC (pMHC) complexes. However, the mechanisms of signaling by TCR-pMHC engagement are not understood.

In the two-year funding period of this R21 grant, the collaboration has set 2 major objectives to begin addressing the precise mechanisms of TCR-pMHC mediated signaling. The first specific aim includes using NMR to analyze the structure of free and pMHC-bound states of the TCR in solution. TCR is a heterodimer of α- and β-chains and this aim should result in the backbone assignment of α- and β-chains in free and pMHC-bound TCRαβ. Because of the large size of the TCR-pMHC complex (100 kDa), this study will benefit greatly from the newly installed 900 MHz NMR spectrometer at IBBR. This cutting-edge instrument was purchased by NIST. Once this information has been ascertained, the second specific aim includes a backbone dynamics analysis of free and pMHC-bound states of TCRαβ. The goal here is to investigate whether pMHC-binding induces allosteric changes in TCR backbone dynamics.

Dr. Orban is a recognized expert in applying high field NMR spectroscopic methods to determine novel protein structures for better understanding the complex relationship between protein sequence and structure. Dr. Mariuzza is internationally recognized for advances in structural immunology with an overall focus on the molecular basis of ligand recognition by cell surface receptors of the immune system. The collaboration between the two groups brings about the ideal expertise to ascertain this complex mechanism for T-cell triggering.