STAT (Signal Transducers and Activators of Transcription) proteins are key elements in the signal transduction pathways of a number of cytokines and growth factors. including IFN-alpha and IFN-gamma. They serve a dual role in these pathways, functioning both as the messenger carrying the signal from the cell membrane into the nucleus and also as the message, activating the transcription of specific genes. Deregulation of these pathways could lead to malignant states arising from uncontrolled proliferation. Given that a cell must simultaneously respond to a myriad of stimuli using these pathways, specificity in transmitting these signals is vital. This specificity is achieved in part through the involvement of STAT proteins in several multiprotein complexes using interactions between a conserved SH2 domain and phosphotyrosine- containing sequences on their partners. Using 13C, 15N, 1H triple- resonance solution NMR methods, structures of the STAT SH2 will be determined in both free and peptide-complexed forms to examine the molecular determinants of specificity in these protein-protein associations. Additionally. structures of a 31kDa STAT SH2 intermolecular dimer will be generated; the formation of this complex in vivo is particularly important for the transduction part of the STAT function. This information will not only provide useful insight into the mechanisms of molecular discrimination in these systems, but also facilitate the rational design of drugs intended to block these interactions.
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