The goal of this research proposal is to study the structure and function of the Lin12/Notch related (LNR) domain of Notch, and to elucidate the role of this region in the regulation of the Notch signaling pathway. Notch proteins are involved in cell growth, differentiation, and death in a variety of tissue types in multicellular organisms. In humans, a subtype of T-cell leukemia and some inherited developmental syndromes are caused by mutations in components of the Notch signaling pathway. Activation of these receptors requires a series of proteolytic events triggered by ligand binding. Notch proteins are restrained in a protease-resistant """"""""resting"""""""" state in part by the LNR domain, a domain containing three LIN12 modules unique to this family of receptors. The mechanism by which the LNR domain regulates proteolytic activation remains unknown. The work described in this research play will provide new insight into the structure and function of the LNR domain in the regulation of Notch receptor activity.
The specific aims of this proposal are: i) to determine how the LNR domain is responsible for the stabilization of the Notch heterodimer (HD), using a molecular biology approach; and ii) to determine the structural and dynamic properties of individual LIN12 modules and/or module pairs, using NMR spectroscopy.
|Sanchez-Irizarry, Cheryll; Carpenter, Andrea C; Weng, Andrew P et al. (2004) Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats. Mol Cell Biol 24:9265-73|