NMR spectroscopic characterization of death domain superfamily proteins: Structures, dynamics and interactions

Death domain superfamily proteins, consisting of death domain (DD), death effector domain (DED), caspase activation and recruitment domain (CARD), and pyrin domain (PYD) subfamilies, are predominantly involved in assembly and activation of apoptotic complexes in the tumor necrosis factor (TNF) receptor-mediated programmed cell death by promoting homotypic protein-protein interactions. Despite low sequence homology across subfamilies, these structural domains are similarly folded into a characteristic antiparallel six-helix bundle structure, and are distinguished by domain-domain interactions and surface features. Death motif superfamily domains possess no catalytic activities, and all their biological functions are exerted through stimulating specific protein-protein interactions within the subfamily and across a wide variety of biological pathways. Structures of member proteins in all four subfamilies have been delineated by NMR spectroscopy and/or X-ray crystallography. Additionally, biologically and functionally relevant protein dynamics and protein-protein interactions using novel NMR techniques have been the focus of most recent studies. In this chapter, we will review recent advances in the NMR characterization of death domain superfamily proteins in the context of structures, dynamics, and interactions, and the implications for these studies in understanding the cellular processes of apoptosis, inflammation, proliferation, and glucose metabolism.