STRUCTURAL ANALYSIS OF THE NFATC CYTOPLASMIC TO NUCLEAR TRANSLOCATION MECHANISM

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Many biological processes are exquisitely sensitive to the level of nuclear occupancy of NFATc proteins. The process of rapid nuclear import and export is regulated by an uncharacterized allosteric switch in the N-terminus of the protein, which regulates the alternate interaction between NFATc proteins and the nuclear import and export machinery. Dephosphorylation by calcineurin unmasks a nuclear localization sequence, allowing interaction with the importin complex and rapid cytoplasmic-to-nuclear translocation. Rephosphorylation in the nucleus induces another conformational change, which exposes the nuclear export sequence (NES) and allows interaction with the nuclear export receptor Crm1. We would like to characterize the mechanism of this allosteric switch by observing differences between dephosphorylated, intermediate and fully phosphorylated states of the N-terminal domain of NFAT.